key: cord-0971864-2qj2rrgd
authors: Lvov, Dimitry Konstantinovich; Shchelkanov, Mikhail Yurievich; Alkhovsky, Sergey Vladimirovich; Deryabin, Petr Grigorievich
title: Chapter 8 Single-Stranded RNA Viruses
date: 2015-12-31
journal: Zoonotic Viruses in Northern Eurasia
DOI: 10.1016/b978-0-12-801742-5.00008-8
sha: 9e5fcbe8ec8b192f8709d43d63e97360732f0d9f
doc_id: 971864
cord_uid: 2qj2rrgd

In this chapter, we describe 73 zoonotic viruses that were isolated in Northern Eurasia and that belong to the different families of viruses with a single-stranded RNA (ssRNA) genome. The family includes viruses with a segmented negative-sense ssRNA genome (families Bunyaviridae and Orthomyxoviridae) and viruses with a positive-sense ssRNA genome (families Togaviridae and Flaviviridae). Among them are viruses associated with sporadic cases or outbreaks of human disease, such as hemorrhagic fever with renal syndrome (viruses of the genus Hantavirus), Crimean–Congo hemorrhagic fever (CCHFV, Nairovirus), California encephalitis (INKV, TAHV, and KHATV; Orthobunyavirus), sandfly fever (SFCV and SFNV, Phlebovirus), Tick-borne encephalitis (TBEV, Flavivirus), Omsk hemorrhagic fever (OHFV, Flavivirus), West Nile fever (WNV, Flavivirus), Sindbis fever (SINV, Alphavirus) Chikungunya fever (CHIKV, Alphavirus) and others. Other viruses described in the chapter can cause epizootics in wild or domestic animals: Geta virus (GETV, Alphavirus), Influenza A virus (Influenzavirus A), Bhanja virus (BHAV, Phlebovirus) and more. The chapter also discusses both ecological peculiarities that promote the circulation of these viruses in natural foci and factors influencing the occurrence of epidemic and epizootic outbreaks

Single-Stranded RNA Viruses

The Bunyaviridae family was named after the prototypical Bunyamwera virus (BUNV) isolated in 1943 from mosquitoes (Aedes spp.) in Bunyamwera, Uganda. 1 Currently, the Bunyaviridae family includes four genera of animal viruses (Orthobunyavirus, Phlebovirus, Nairovirus, and Hantavirus) and one genus (Tospovirus) of plant viruses. 2 Bunyavirus virions are spherical in shape (size, about 80À120 nm) and have an outer lipid bilayer with the viral envelope glycoproteins Gn and Gc exposed on the surface. The genome consists of three segments of single-stranded, negative-sense RNA with a total length from 11,000 to 19,000 nt. Depending on the size, the segments are designated L (large), M (medium), and S (small). The viral proteins are synthesized on the mRNA that is produced during replication and that is complementary to the genomic RNA. The length of segments varies for different genera, but in general, they have a common structure. The L-segment, whose length is from 6,400 nt (Phlebovirus) to 12, 200 nt (Nairovirus) , has a single open reading frame (ORF) encoding RNA-dependent RNA polymerase (RdRp). The M-segment of all of the genera also has a single ORF, which encodes a polyprotein precursor of envelope glycoproteins Gn and Gc. The length of the M-segment ranges from 3,288 nt for some of the phleboviruses to 4,900À5,366 nt for the nairoviruses. The mature glycoproteins Gn and Gc of the bunyaviruses are derived during complex endoproteolytic events leading to cleavage of the polyprotein precursor by cellular proteases. The S-segment of the bunyaviruses encodes a nucleocapsid protein. Additional nonstructural (NSs) protein is encoded by the S-segment of viruses of the Phlebovirus, Tospovirus, and Orthobunyavirus genera. 2, 3 The bunyaviruses are widely distributed in the world and are one of the most numerous known zoonotic viruses. Most of the zoonotic bunyaviruses are transmitted to animal or humans by bloodsucking arthropod vectors, usually mosquitoes or ticks. Viruses of the Hantavirus genus are the exception, being transmitted mainly by aerosol formed from virus-laden urine, feces, or saliva of infected rodents or insectivores that are their natural hosts. 4À6

The genus Hantavirus consists of those bunyaviruses of vertebrates which do not have the ability to replicate in an arthropod's cell and which are transmitted by respiratory route through the formation of aerosols from urine or feces containing the virus. 1 The morphology of the virion and the genome structure of the hantaviruses are common to all bunyaviruses. The size of the negative-sense ssRNA genome of the prototypical Hantaan virus (HTNV) is 6,533 nt for the L-segment, 3,616 nt for the M-segment, and 1,696 nt for the S-segment (Figure 8 .1). 1 In nature, hantaviruses persist asymptomatically in rodents and insectivores, with each type of hantavirus associated predominantly with one host species. The phylogenetic relationships of hantaviruses enable virologists to divide them into three lineages, which correspond in general to their main hosts. In the S-segment of some hantaviruses carried by Arvicolinae and Sigmodontinae rodents, there is an additional ORF-encoded nonstructural protein NSs. But NSs is absent in the hantaviruses of the Murinae rodents. 2À4

History. Hemorrhagic fever with renal syndrome (HFRS) was originally described as a separate nosological category (called "endemic (epidemic) hemorrhagic nephroso-nephritis" at that time) by Anatoly Smorodintsev (Figure 2 .11) during 1935À1940 in the Far East. Later, Japanese scientists described HFRS in northeastern China as "Songo fever" and Swedish scientists as "epidemic nephropathy"; a similar disease was described in 1960 in China. 1 The abbreviation "HFRS" was suggested by Mikhail Chumakov (Figure 2 Korea. 2 Hantaviruses. The hantaviruses are members of the Hantavirus genus of the Bunyaviridae family. The first serotype, -HTNV, included strains isolated from mouselike rodents (Muridae) in South Korea, China, and the southern part of the Russian Far East (Primorsky Krai). 2À4 The second serotype, Puumala virus (PUUV), was isolated from hamsterlike rodents (Cricetidae), mainly the bank vole (Myodes glareolus) in Finland and then in other European countries and the western part of Russia, as well we from Maximowicz's vole (Microtus maximoviczii) in the Far East). 5À8 The third serotype, Seoul virus (SEOV), was isolated from brown rats (Rattus norvegicus), black rats (Rattus rattus), and laboratory albino rats (Rattus norvegicus f. domestica) in South Korea and elsewhere, including the United States. 3, 4 The fourth serotype, DobravaÀBelgrade virus (DOBV), was isolated from the striped field mouse (Apodemus agrarius) in Slovenia 9 and Yugoslavia. 10 The fifth serotype, Sin Nombre virus (SNV), literally "nameless virus" in Spanish, was isolated from the meadow vole (Microtus pennsylvanicus). 8 In addition to the 5 main serotypes, 15 other serotypes are known today, including 6 in Eurasia: Amur virus (AMRV), isolated from Asiatic forest mice (Apodemus peninsulae) in the Far East of Russia 11 and in China 12 ; Tula virus (TULV), from common voles (Microtus arvalis) in central Russia 13, 14 ; Khabarovsk virus (KHAV), from from reed voles (Microtus fortis) and Siberian brown lemmings (Lemmus sibiricus) in the Far East 15 ; Thottapalayam virus (TPMV), from Asian musk shrews (Suncus murinus) in India 16 ; Thailand virus (THAIV), from bandicoots (Bandicota indica) in Thailand 17 ; and a newfound hantavirus, from Chinese mole shrews (Anourosorex squamipes) in Vietnam. 18 Virion and Genome. The size of the negative-sense ssRNA genome of the prototypical HTNV is 6,533 nt for the L-segment, 3 ,616 nt for the M-segment, and 1,696 nt for the S-segment (Figures 8.1 and 8.2 ).

Epizootiology. Rodents (order Rodentia) are the main natural reservoir of hantaviruses. Nevertheless, strains have been isolated from birds in the Far East 19 and from bats in China. 20 Infection in rodents is asymptomatic, but the virus is expelled with saliva, urine, and excrement, most intensively during the first month after inoculation. (During this period, virus antigen can be detected in the lungs.) 4 The evolution of hantaviruses is closely related to that of its rodent host (Figure 8 .2). 4, 6, 21 At least 34 species of rodents (Rodentia), 2 species of lagomorphs (order Lagomorpha), 7 species of insectivores (order Insectivora), 1 species of predators (order Carnivora), and 1 species of artiodactyls (order Artiodactyla) are known to take part in hantavirus circulation on the territory of Northern Eurasia. 8, 21, 22 The main species of rodents, which are the hosts of hantaviruses in Russia, are presented in Table 8 .1. The infection rate of mouselike rodents and insectivores lies within the limits 3.3 6 0.5%. 23 Hantavirus antigens have been detected in birds as well: the Oriental turtle dove (Streptopelia orientalis), coal tit (Parus ater), marsh tit (Parus palustris), Daurian redstart (Phoenicurus auroreus), nuthatch (Sitta europaea), black-faced bunting (Emberiza spodocephala elegans), Eurasian jay (Garrulus glandarius), hazel grouse (Tetrastes bonasia), pheasant (Phasianus colchicus), Ural owl (Strix uralensis), green-backed heron (Butorides striatus), and grey heron (Ardea cinerea). 19 Hantavirus (Magboi virus, or MGBV) was isolated in 2012 from the hairy slit-faced bat (Nycteris hispida) in Africa (Sierra Leone), 24 but the role of bats in the circulation of hemorrhagic fever with renal syndrome virus (HFRSV) is yet to be investigated in detail.

In western Siberia, the main natural reservoir of HFRSV is rodents of the hamsterlike (Cricetidae) family-in particular, bank voles (Myodes glareolus), with a susceptibility up to 70%; red-backed voles (Myodes rutilus), susceptibility 9%; and, in the north, Siberian brown lemmings (Lemmus sibiricus), 14%. The infection rate of other rodents and insectivores is about 0.4À3.0%. 8, 22 In eastern Siberia, the maximum susceptibility is demonstrated in grey red-backed voles (Myodes rufocanus), 70%; house mice (Mus musculus), 15%; water voles (Arvicola terrestris), 8%; and tundra voles (Microtus oeconomus), 8%. 8 In the Far East, HFRSV was revealed to circulate among field mice (Apodemus agrarius) with a susceptibility of about 35%; Asiatic forest mice (A. peninsulae), susceptibility 30%; reed voles (Microtus fortis), 4À18%; grey redbacked voles (Myodes rufocanus), 12%; and other rodents (Rodentia), 0.7À4.3%. 21, 22, 25 Epidemiology. HFRSV infection starts by aerogenic penetration of the virus during the inhalation of waste products (saliva, urine, excrement) of latently infected animals. An alimentary pathway (with contaminated food and water) of the infection is also possible. 4, 8, 22, 26, 27 HFRS is distributed over Eurasia (Russia, Belarus, Ukraine, Moldova, the Baltic countries, the Czech Republic, Slovakia, Bulgaria, Romania, Serbia, Slovenia, England, France, Germany, Belgium, Hungary, Denmark, Fennoscandia, Kazakhstan, Georgia, Azerbaijan, China, North and South Korea, Japan), as well as American and African countries. 7, 28, 29 During 2000À2009, in 58 of 83 regions in Russia, 74,890 cases of HFRS were registered (Table 8 .2). 8 Annual morbidity of HFRS in Russia is in the range from 2,700 to 11,400 cases (1.3À7.8%) and is decreasing. About 95% of cases take place in European forest landscapes. PUUV associated with the bank vole (Myodes glareolus) provokes about 90% of HFRS cases in Russia (especially in Bashkortostan, Udmurtia, Mari El, Tatarstan, the Chuvash Republic, Orenburg, Ulyanovsk, and the Penza region). 8, 30 Morbidity in the urban population is higher (65%) than in the rural one. The peak of the disease occurs during JulyÀOctober in forests and in gardens and kitchens closely situated to the forests. 4 ,31À33 DOBV associated mainly with field mice (Apodemus agrarius) and small forest mice (A. uralensis) is of leading epidemiological significance in the central and southwestern sectors of the European part of Russia (the Voronezh, Lipetsk, Orel, and Belgorod regions), as well as in Georgia. 8, 31, 34, 35 PUUV and TULV are associated with the common vole (Microtus arvalis) and the bank vole (Myodes glareolus) and are also distributed over this territory. 4, 8, 36 A similar situation is observed in other regions of the Central Federal District: in the Moscow, Yaroslavl, Ryazan, Tver, Kaluga, Vladimir, Ivanov, Kostroma, Smolensk regions. HFRS morbidity in the Moscow region is associated with PUUV, 31 the infection rate of which is 12À57% among bank voles (Myodes glareolus), 10À20% in the common vole (Microtus arvalis), 11% in Major's pine vole (Microtus majori), and in 4À6% other rodent species. 1 In Krasnodar Krai, the Black Sea field mouse (Apodemus ponticus) and Major's pine vole (Microtus majori) play the main role in human morbidity. 31, 37 Human morbidity in the European part of Russia is registered beginning at a relatively low level in MarchÀApril, decreasing to yet a lower level in MayÀAugust, increasing in SeptemberÀNovember, and then increasing again during DecemberÀJanuary. 1 The hyperendemic territory is the southwestern Ural region (especially the Bashkortostan Republic and the Chelyabinsk and Orenburg regions), the Volga-Vyatka economic region (especially the Udmurt Republic), the Chuvash Republic, and the Tatarstan, Mari El, Samara, Penza, Saratov, and Ulyanovsk regions. 4, 8 The main human morbidity occurs among those 20À40 years old (chiefly men). In Russia, HFRS represents a significant part of all naturalfoci zoonotic diseases. The immune layer to HFRSV in the European part of Russia is a mean 4.7%; in the Bashkortostan Republic, it reaches up to 40% (mean, 17%). 4 The immune layer among the populations of western and eastern Siberia is about 2% for the entire region, 0.2% in Krasnoyarsk Krai, 1.1% in the Irkutsk region, 3.1% in the Omsk region, and 12.6% in the Tyumen region. 1, 4 The Far East provides about 2% of all HFRS cases in Russia. 23 The highest morbidity was revealed in Khabarovsk Krai, Primorsky Krai, and the Amur region. 1 In Khabarovsk Krai and Primorsky Krai, las in China and Japan, -HTNV is associated with grey red-backed voles (Myodes rufocanus). 2, 3, 21, 37 The morbidity of SEOV (the third serotype) associated with the synanthropic brown rat (Rattus norvegicus) and black rat (R. rattus) was examed in both the Far East and the European part of Russia. The researchers found that SEOV provoked HFRS more often among the urban population, whereas HTNV did so more often among the rural population, of Primorsky Krai. 21 Morbidity in the Far East has a small uptick in MayÀJuly and reaches its main peak in NovemberÀDecember. The immune stratum in the Far East is about 1% (ranging from 0.3% in the Amur region to 1.5% in Primorsky Krai). 1, 21 Pathogenesis. Capillary damage is the basis of HFRS pathogenesis. In the first part of the disease, toxicoallergic phenomena predominate, caused by viral infection of the walls of vegetative centers, venules, and arterioles. Lesions on the sympathetic nodes of the neck are followed by hyperemia of the face and neck. Irritation of the vagus nerve leads to bradycardia and a fall in arterial pressure. Damage to the vascular permeability is accompanied by hemorrhages in mucous membranes and the skin. The cause of death is cardiovascular insufficiency, massive hemorrhages into the vital organs, plasmorrhea into the tissues, collapse, shock, swelled lungs, spontaneous rupture of the kidneys, a hypertrophied brain, and paralysis of the vegetative centers. 4, 22 Clinical Features. The incubation period is 4À30 days. HFRS starts with fever, headache, muscular pain, dizziness, nausea, vomiting, hyperemia of the face and neck, bradycardia, and a fall in arterial pressure. Abnormalities of the central nervous system (CNS) in the form of block, excitement, hallucinations, meningeal signs, and visual impairments often occur. Hemorrhagic syndrome becomes apparent as plasmorrhea into the tissues, together with microthrombosis; exanthema; petechial skin rash; nasal, pulmonary, and uterine bleeding: vomiting blood, hematuria, and visceral bleeding. In some cases, Pasternatsky syndrome, pain in the kidneys, oliguria, and albuminuria become morphologically apparent as interstitial and tubular nephritis. The duration of fever is 3À9 days. Two-wave temperature dynamics is possible. 22, 38 Analyses of 5,282 cases of HFRS etiologically linked with PUUV in Sweden during 1997À2007 found 0.4% mortality in the first three months of the disease. 39, 40 Defense immunity remains for at least 30 years. 8, 22 Diagnostics. Laboratory diagnostics are based on the fluorescent antibody method (FAM), enzyme-linked immunosorbent assay (ELISA), and reverse transcription polymerase chain reaction (RT-PCR) testing. The virus can be isolated with the use of Vero E6 (green monkey kidney cell line), 2Bs (diploid human embryo lung cell line), A-549 (human lung carcinoma cell line), or RLC (rat lung tissue primary cell culture). 8, 22 Control and Prophylaxis. Treatment of HFRS can be symptomatic, pathogenetic, or etiotropic (or any combination thereof). During the fever period, early hospitalization, disintoxical therapy, and strengthening of the walls of vessels are necessary. During the oliguria period, transfusion with desalinated human albumin, hemodes, a 5% glucose solution, and an isotonic NaCl solution (under the control of the emitted volume of urine) are given. In case of shock, antishock therapy is applied, and hemodialysis is prescribed for kidney insufficiency. 4, 22 Vaccination is the most effective approach to the prophylaxis of HFRS. The efficacy of vaccination was demonstrated in China and in North and South Korea. Nevertheless, it must be mentioned that vaccines in these countries are produced from HTNV and SEOV stains and do not defend against PUUV infection, which is the main etiological agent of HFRS in the European part of Russia (where 98% of all Russian morbidity occurs) 8 .

For a long time, anti-HFRS vaccine was difficult to produce because there were no sensitive cell lines to accumulate hantavirus. However, the recent adaptation of PUUV and DOBV to the certified Vero E6 cell line affords an opportunity to produce candidate vaccines against HFRS. Experimental series of "Combi-HFRS-Vac" vaccine have passed compliance tests for medical immunoglobulin preparations for use in humans. 8, 41, 42 

The genus Nairovirus includes the ticktransmitted bunyaviruses, whose genome is the largest in the family Bunyaviridae. The size of L-segments of the Dugbe virus (DUGV), a prototypical species of the nairoviruses, is 12,255 nt. The M-and S-segments are 4,888 and 1,716 nt, respectively (Figure 8 . 3) . As with other bunyaviruses, the L-segment of the nairoviruses encodes an RdRp, the M-segment encodes a polyprotein precursor of the envelope glycoproteins Gn and Gc, and the S-segment encodes the nucleocapsid (N) protein. 1, 2 The genus Nairovirus was established on the basis of antigenic relationships among viruses of the six antigenic groups of arthropod-borne viruses: the CrimeanÀCongo hemorrhagic fever (CCHF), Nairobi sheep disease (NSD), Qalyub (QYB), Sakhalin (SAK), Dera Ghazi Khan (DGK), and Hughes (HUGV) groups. 3À6 Subsequently, a seventh, Thiafora (TFA), group was assigned to the genus. 7, 8 Currently, about 35 viruses are assigned to the genus Nairovirus, now united in the aforementioned seven groups. 1 Sequence analysis of previously unclassified bunyaviruses revealed that the nairoviruses actually number much more than 35 . Three additional groups of nairoviruses-Issyk-Kul (ISK), Artashat (ARTSV), and Tamdy (TAM)-were established on the basis of phylogenetic analysis (Table 8 .3).

CCHFV belongs to the Nairovirus genus of the Bunyaviridae family and is the etiological agent of CrimeanÀCongo hemorrhagic fever (CCHF). History. CCHF was first mentioned as "hunibini" and "hongirifta" by Tajik physician Abu-Ibrahim Djurdjani in the twelfth century. The viral nature of CCHF was originally established in 1945 during an expedition to Crimea headed by Mikhail Chumakov at the time of an outbreak. 1À3 The modern history of CCHFV investigation starts in June 1944 with an epidemic of the disease in the northwestern steppe part of the Crimean Peninsula. More than 200 severe cases of the disease broke out, all exhibiting hemorrhagic syndrome, known in that time as "severe infectious capillary toxicosis." Mikhail Chumakov headed an expedition to the region, and much research revealed that the disease is transmitted by Hyalomma plumbeum (marginatum) ticks of the Ixodidae family. The disease 1 In 1963, the historical Hodzha strain was isolated from a patient with hemorrhagic fever in Uzbekistan, as was a set of strains from H. marginatum larvae and nymphs in the Astrakhan region, near the Caspian Sea. 2, 3 In 1967, the similarity between the etiological agent of Crimean hemorrhagic fever and that of Congo virus, isolated from a patient in 1966 in Zaire (Congo), was demonstrated, so the virus was renamed CCHFV. 4, 5 Genome and Taxonomy. Like the genomes of all nairoviruses, that of CCHFV consists of three segments of negative ssRNA: a signed small (S) (1,672 nt) segment, a medium (M) (5,366 nt), and a large (L) (12,108 nt) segment. Each segment has a single ORF that encodes the nucleocapsid protein (N, 482 aa, S-segment), a polyprotein precursor of envelope glycoproteins Gn and Gc (1,684 aa, M-segment), and RdRp (3,945 aa, L-segment).

Genetic diversity among CCHFV strains may reach 31% nt and 27% aa differences for M-segment sequences, a reflection of pressure on the immune system and adaptation to various ecologic zones with different prevalences of Hyalomma tick species. The S-and L-segments are more conservative: The level of divergence of S-segment sequences is 20% nt and 8% aa, and that for L-segment sequences is 22% nt and 10% aa.

Phylogenetic analysis based on sequence data comparisons of S-segments shows that CCHFV isolates from different regions can be clustered into seven phylogeographic groups: West African isolates (group I), as well as isolates from Central Africa (Uganda and the Democratic Republic of the Congo) (group II); South Africa and West Africa (group III); the Middle East and Asia (group IV) (the Asian strain can be divided to two distinct subgroups: Asia 1 (IVa) and Asia 2 (IVb)); Europe and Turkey (group V); and Greece (group VI), a separate group detached from the rest of Europe (Figure 8.4) . 6À8 In general, the genotypic structure defined on basis of the S-segment analysis is correlated strictly with geography. Cases of isolation of strains not typical for a given territory were attributed to possible transmission of the virus by infected ticks carried by migratory birds. The tree topology based on the L-segment comparison is, on the whole, similar to that generated on the basis of the S-segment. Exceptions are the viruses from Senegal, which represent a separate lineage in the S-segment analysis, and those clustered within group III in the L-segment analysis. Similarly, the division of group IV into group IVa (Asia 1) and IVb (Asia 2) is not clear (Figures 8.5 and 8.6) .

In Russia, most of the strains of CCHFV that were isolated were isolated in the country's southern regions (Astrakhan, Volgograd, and Stavropol districts). Phylogenetic analysis showed that all of them are closely related to European and Turkish strains (group V). 9À12 Epizootiology. Up to today, CCHFV has been found to circulate in 46 countries in Europe, Africa, and Asia. 4,13À15 CCHFV was isolated from at least 27 species of mainly Ixodidae ticks, but their roles in maintaining virus circulation are different (Tables 8.4 and 8.5). The main significance for CCHFV reservation and transmission belongs to ticks of the Hyalomma genus: H. marginatum in the south of he European part of Russia, H. anatolicum and H. detritum in the Middle East and Asia, and H. asiaticumin Kazakhstan. According to our data, the viral load among imagoes of H. marginatum in the Astrakhan region in 2001À2005 was 1.33%; among nymphs, the load was 0.2%. The presence of transphase and transovarial transmission of CCHFV provides a reservation for viruses during the interepidemic period. Three hostsfor larvae (ground birds, mainly Corvidae; TABLE 8.4 Isolation of CCHFV from Ixodidae Ticks mouselike rodents; and hares), nymphs (also ground birds, mouselike rodents, and hares), and imagoes (large mammals-mainly cattle, sheep, and camels)-provide a variety of ecological links of CCHFV to vertebrates. 1,16À19 In Nigeria, CCHFV was isolated from midges (Culicoides sp.) 4 The distribution of H. marginatum is limited by the isotherm of effective temperatures such that sum (Σ T $ 10 C ) 5 3,000 C, or 120 days with mean temperature $20 C per year. 20 So, the northern boundary of the distribution of CCHFV in the south of the European part of Russia lies in the dry steppe subzone. 1 In Russia and South Africa, CCHFV is often isolated from hares. 1, 21 CCHFV was isolated from hedgehogs (Atelerix spiculus) in Nigeria. Hares and mouselike rodents play the main role in CCHFV circulation. 1, 21, 22 Viremia in birds is not sufficient for vector transmission (although specific antibodies appear); nevertheless, ground birds are an important element of CCHFV transmission because they are the hosts for the preimaginal phases of H. marginatum development. 16, 18, 23 During field investigations of Chatkalsky Ridge in Kirgizia, nymphs and larvae of H. marginatum dominated among field-collected materials from birds. The highest number of ticks was found on rollers (Coracias garrulus), crested larks (Galerida cristata), tree sparrows (Passer montanus), and blackbilled magpies (Pica pica). In the Astrakhan region, rooks (Corvus frugilegus) are the main hosts for H. marginatum preimaginal phases. 16 During migrations, birds can take part in dispersing preimago ticks that carry the virus. For example, in Spain in 2010, CCHFV of African origin (probably introduced by migrating birds) was isolated from H. lusitanicum. 24 European birds overwintering in Africa were also found to harbor ticks that carried the virus. 25 CCHFV infection rates found as the result of an investigation of 40,711 domestic animal sera are presented in Table 8 .6. 20 Domestic animals are one of the main reservoirs of CCHFV among vertebrates. Viremia (2.6À3.7 (log 10 LD 50 )/20 mcL) sufficient for the infection of ticks was detected 5À8 days after experimental inoculation of sheep. Viremia after up to 10 days post inoculation was detected in small gophers (Citellus pygmaeus), long-eared hedgehogs (Hemiechinus auritus), and wood mice (Apodemus sylvaticus). Experimental infection was revealed only in nymphs, and that is why hares and Corvidae birds-the main hosts for nymphs-play the chief role in CCHFV circulation. Astrakhan  1  5  11  13  9  4  37  16  20  5  6  7  10  7  1  152   Volgograd  0  18  9  3  3  2  6  16  30  7  2  3  0  0  6  105   Dagestan  0  6  10  7  3  1  3  3  2  2  1  3  2  0  2 Rostov  27  0  5  7  9  9  16  55  53  83  27  16  48  41  38  434   Stavropol  10  48  21  54  30  41  38  41  63  80  66  28  26  24  32  602   Krasnodar  0  0  0  0  0  0  1  0  0  0  0  0  0  0  0  1   Total  38  85  59  97  77  76  139 200 234 193 119 67  97  75  79  1,635 of Ixodidae (at first, H. marginatum) ticks in this region as the result of climatic changes. During 1999À2010, 13,838 cases of CCHF 44 were recorded in Russia, including 520 in Stavropol Krai, 45 307 in the Rostov region, 46 276 in the Kalmyk Republic, 47 134 in the Astrakhan region, 48 99 in the Volgograd region, 49 41 in the Dagestan Republic, 5 in the Ingush Republic, and 1 in the KarachaevoÀCherkesskaya Republic 50 (Table 8 .7). In 2013, 80 cases of CCHF were recorded on the territory of the Southern Federal District and the North Caucasian Federal District (Table 8 .8, Figure 8 .8). The absence of any recorded cases of CCHF in Krasnodar Krai could be explained by a lack of attention to CCHF diagnostics.

A decrease in the proportion of severe clinical forms with hemorrhagic syndrome occurred after 2006. The drop could have been due to the introduction of high-grade express diagnostics methods into clinical practice and an intensification in seeking out and diagnosing those suspected of having CCHF. At the same time, the disease extended its incidence into the new territories of the Volgograd region, with nosocomial CCHF cases recorded there once again. 52 Pathogenesis. Pathogenesis is defined by lesions of the vascular and nervous systems. 17, 51, 53 Clinical Features. The incubation period after transmissive CCHFV inoculation (as the result of a tick bite) is 2À7 days, whereas that after contact inoculation is 3À4 days. The difference is due to a much higher quantity of virus entering the system during contacts inoculation. 17, 50, 53 CCHF starts rapidly, with the temperature increasing to 39À40 C and the appearance of fever, skin hyperemia in the top half of the trunk, headache, lumbar pain, abdominal and epigastric pains, generalized arthralgia, conjunctivitis, pharingitis, and diarrhea. About 50% of cases have two obvious waves of increasing temperature, with the temperature decreasing in 6À7 days after the end of the incubation period. Petechial rash appears in the majority of all CCHF patients in 3À4 days after the incubation period and is a marker of the second increasing-temperature wave. Hemorrhagic diathesis with nasal bleeding (in two-thirds of cases), bloody vomiting, blood in the sputum, and hematuria, all starting 3À5 days after the end of incubation period, are characteristic in 85% of cases. The duration of the hemorrhagic period is 8À9 days. Meningitis symptoms and signs of psychosis (depression, sleepiness, lassitude, photophobia) could develop as well. Lethality is 16À20% for transmissive inoculation and up to 50% for contact inoculation. Nevertheless, lethality is decreasing as the result of the introduction of modern testing systems and treatment with ribavirin. The convalescent period is about a month. 17, 50, 51, 53 E.V. Leshchinskaya has suggested the following clinical classification of CCHF: (i) severe form with hemorrhagic syndrome (1.a. without band bleeding; 1.b. with band bleeding); (ii) without hemorrhagic syndrome (2.a. medium-severe form; 2.b. light form). 50, 53 Diagnostics. Diagnosis is based on the detection of both specific antibodies via ELISA (IgM after 8 days post disease progression and IgG) and virus RNA via RT-PCR testing (earlier than 8 days post disease progression). 43, 54 Both tests must be conducted for a definitive diagnosis of CCHF to be made. During the first week of infection with CCHF, positive results via RT-PCR are obtained in 93% of cases; during the second week, the percentage is 40%. During the second week of the disease, positive results in IgM via ELISA are obtained in 93% of cases; during the third week, the percentage of positive reults in IgG via ELISA is 80%. 55À58 Control and Prophylaxis. Ribavirin is the most effective drug prescribed today. 53 ,59À61 Ribavirin is used for 5 days after symptoms first appear: 2,000 mg (10 capsules) or 30 mg/kg for the first time, then 600 mg 3 2 times a day if the weight of the patient is more than 75 kg or 500 mg 3 2 times a day if the weight of the patient is is less than 75 kg). The duration of treatment is 4À10 days. Ribavirin must not be used by pregnant women, except when the disease is considerd life threatening.

Vaccine development is currently just in the experimental stages, 62À64 so prophylaxis involves early detection of sick humans and the prevention of further contact infections. Nonspecific prophylaxis includes the eradication of Ixodidae ticks on livestock and acaricide treatment of locations inhabited by domestic animals. In pastures with large numbers of Ixodidae ticks, animals have to be led into box stalls and the humans leading them there must use special suits.

History. Artashat virus (ARTSV, strain LEIV-2236Ar) was originally isolated from Ornithodoros alactagalis ticks (family Argasidae) collected in the burrows of a small five-toed jerboa (Allactaga elater) near Arevashat village (40 02 absence of antigenic relationships with any known viruses, it was referred to as an "unclassified bunyavirus." 1À3 Taxonomy. Three strains of ARTSV were sequenced. 4 A full-length genome comparison revealed that ARTSV has 42À60% nt similarity to other nairoviruses. Phylogenetic analysis revealed that the virus is a new species in the Nairovirus genus and forms a distinct genetic lineage on the nairovirus tree, which was constructed for all three segments of the genome (Figures 8.10À8 . 12) .

The phylogeny of the nairoviruses is based mainly on analyses of the partial sequence of the conservative catalytic core domain of RdRp. 5, 6 The similarity of this domain of ARTSV to other nairoviruses is 42À65% nt and 58À70% aa. The phylogenetic tree constructed by the maximum-likelihood method on the basis of the amino acid alignment of the RdRp catalytic core domain of nairoviruses confirms the topology of ARTSV on a newly formed genetic lineage (Figures 8.10À8.12 ). The nairoviruses on the tree can be divided into two main phylogenetic groups. The first group includes the nairoviruses, which are transmitted predominantly by ixodids: the CrimeanÀCongo hemorrhagic fever group (Hyalomma and Haemaphysalis, as well as Dermacentor, Rhipicephalus, and Ixodes), the Dugbe group (mainly Amblyomma, but also Hyalomma, Rhipicephalus, and Haemaphysalis), the Sakhalin group (Ixodes), and the Tamdy group (Hyalomma). The first group also includes Erve virus (ERVEV), whose vectors are unknown. 7, 8 The second phylogenetic lineage includes the nairoviruses from the Hughes, Issyk-Kul, Dera Ghazi Khan, and Qalyub groups, whose vectors are argasids: Argas and Ornithodoros. The tree topology of ARTSV shows that the virus is in the lineage of the nairoviruses transmitted predominantly by Ixodidae ticks, although all isolations of ARTSV were obtained from the Argasidae ticks O. alactagalis and O. verrucosus (Table 8.9 ). It can be assumed that the adaptation of ARTSV to argasids is the result of the the narrow ecologic niche occupied by those ticks, which are ticks of the subgenera Theriodoros and Pavlovskyella. Note that, although ERVEV, a European nairovirus, is phylogenetically close to the nairovirus transmitted by ixodids, the association of ERVEV with Ixodes spp. ticks has not been established in endemic areas (southern Europe). 8 ERVEV has been isolated from shrews (Crocidura russula). 9 Arthropod vectors. The adaptation of viruses to Argasidae ticks facilitates the possibility of survival of viral populations in winter at low temperatures and in dry periods. The ability of argasids to fast (up to 9 years and more), the long life cycle of these ticks (up to 20À25 years), and their polyphagia and ecological plasticity determine the stability of the natural foci of arboviruses transmitted by argasids. These foci are confined mainly to the arid regions of the southern part of the temperate and subtropical zones. 1, 2, 10 The northern border of the range of argasids coincides with isolines denoting a frost-free period of 150À180 days per year and an average daily temperature above 20 C for no less than 90À100 days per year. 11 Tick species from the subgenera Theriodoros (Ornithodoros alactagalis, O. nereensis) and Pavlovskyella (O. papillipes, O. verrucosus, O. cholodkovskiy, O. tartakovskiy) are associated mainly with burrows of rodents. 11 This ecological peculiarity narrows the possibility of the spread of viruses that are adapted to ticks from the Theriodoros and Pavlovskyella subgenera. 2 It also applies to ARTSV associated with burrowÀ shelter biomes and found only in Transcaucasia.

History. Caspiy virus (CASV, prototypical strain LEIV-63Az) was originally isolated from the blood of a sick herring gull (Larus argentatus) caught on Gil Island in the Baku archipelago, off the western coast of Azerbaijan in the Caspian Sea (40 17 0 N, 49 55 0 E; Figure 8 .13) in 1970. 1À4 On the basis of electron microscopy, CASV was classified as a member of the Bunyaviridae family, but antigenic relationships with known bunyaviruses have not been found. Thus, CASV was categorized into the unclassified bunyaviruses. 5,6À8 At the same time, and in the same place, three strains of CASV were isolated from Ornithodoros capensis (family Argasidae) ticks Taxonomy. The genome of the prototypical strain LEIV-63Az of CASV was sequenced, and it has been shown that CASV is a member of the HUGV group of the Nairovirus genus. 11 The S-segment of CASV is about 1,594 nt in length and has a single ORF that encodes the nucleocapsid protein (N, 497 aa). The second start codon, in position 7, is located in the N-protein ORF of CASV. The identity of the amino acid sequence of the N-protein of CASV with those of other nairoviruses is only 28%, on average. The cleavage site for caspase-3 (D285EVD288) that has been found in the N-protein of CCHFV is absent in CASV. Cleavage of N by caspase-3 is required for effective replication of CCHFV. 12 Note that caspase cleavage sites in the nucleocapsid protein are also necessary for replication of human influenza A viruses. 13 The M-segment of CASV, like that of the other nairoviruses, has a single ORF-encoded polyprotein precursor of the envelope glycoproteins Gn and Gc. The length of the Gn/Gc precursor of CASV is 1,376 aa. According to the results of an analysis of polyprotein in the program SignalP server 4.1, the first 32 aa constitute the signal peptide that is cleaved on the SSA/SY site. The cleavage site between pre-Gn and pre-Gc is in position 699 (VSG/IK). These data are confirmed by the location of transmembrane domains in mature proteins Gn and Gc that was defined with the use of the program TMHMM server 2.0. Six potential sites of N-glycosylation are predicted in the mature Gn protein of CASV, only one in the Gc protein.

In general, the level of identity of polyprotein in CASV is 25À27% aa with that of other members of the Nairovirus genus (Table 8. 3). The L-segment of CASV has an ORF (4,001 aa) that encodes the viral enzyme RdRp, which is the most conservative viral protein. The similarity of the RdRp of CASV to that of other nairoviruses for which complete genome sequences were available is 38.8À43.0% aa.

Phylogenetic analysis based on the predicted full-length amino acid sequences revealed that CASV is equidistant from other nairoviruses, and forms a distinct branch, on the trees (Figures 8.10À8.12). For many nairoviruses, only short sequences of the catalytic core domain of RdRp are available in GenBank. This domain of RdRp is very conservative and relevant to phylogenetic analysis. 1, 14, 15 The highest level of similarity (80% aa) that the RdRp core domain of CASV has is with the same sequences in viruses of HUG. On the dendrogram, constructed on the basis of a comparison of RdRp core domains, CASV is located on the branch of the HUG group (Figures 8.10À8.12 ). Note that viruses of this group (as well as CASV) have been isolated from Ornithodoros (Carios) ticks that are associated with seabirds on the coasts and islands of the world's oceans. 2, 16 Thus, the phylogenetic relationship of CASV with HUG group viruses reflects the ecological features of those coasts and islands.

Arthropod Vectors. Ornithodoros capensis ticks inhabit the coasts and islands of the Atlantic, Indian, and Pacific Oceans from the southern part of the temperate zone to the equator, as well as some large inland ponds. 3 3, 4, 17 O. capensis ticks feed on many bird species, mainly those of the order Charadriiformes: gulls (family Laridae) and terns (Sturnidae), but also cormorants (Phalacrocoracidae) and pelicans (Pelecanidae). 4, 17 These argasid ticks have a life cycle made up of six to eight stages: egg, larva, three to five stages of nymphs, and imago. According to laboratory study, the cycle is from 43 to 83 days and so can be completed during a single breeding season. These ecological peculiarities provide stability to the natural foci of the viruses, which are adapted to the O. capensis tick viruses and their transcontinental transfer by migrating birds. 5 Vertebrate Host. In 1970, during the collection of field material on islands in the Baku archipelago, an epizootic among herring gulls was observed. The first strain of CASV was isolated from sick birds. Migrations in search of food, including migration between the western and eastern coasts of the Caspian Sea, result in a sharing of the argasids and viruses ranging over the area.

History. The prototypical strain LEIV-858Uz of the Chim virus (CHIMV) was isolated from Ornithodoros tartakovskyi ticks collected in July 1971 in the burrows of great gerbils (Rhombomys opimus) in the vicinity of the town of Chim in the Kashkadarinsky region of Uzbekistan) (38 47 0 N, 66 18 0 E; Figure 8 .14). 1À3 Isolation of CHIMV was carried out during monitoring of these arboviruses' foci on the territory of central Asia and Kazakhstan. CHIMV was investigated through serological testing with viruses from different families and with unclassified viruses isolated earlier in the USSR. Because no antigenic relationships of CHIMV were (and still have not been) found, CHIMV was assigned to the category of unclassified viruses. 3, 4 Later, four strains of CHIMV were isolated from the ticks O. tartakovskyi, O. papillipes, and Rhipicephalus turanicus (Rhipicephalinae) respectively collected in the burrows of great gerbils in the Kashkadarya, Bukhara, and Syrdarya districts of Uzbekistan in 1972À1976. 5, 6 Three strains of CHIMV also were isolated from Hyalomma asiaticum (Hyalomminae) ticks and from the livers of great gerbils, which were collected in the floodplains of the Or River and Karatal River (Dzheskazgan district, Kazakhstan) in April 1979 (Figure 8 .14). 7, 8 Taxonomy. The genome of the prototypical strain LEIV-858Uz of CHIMV was sequenced, and, on the basis of sequence analysis, the virus was classified as a novel member of the Nairovirus genus. 9 Phylogenetic analysis based on a partial sequence of a catalytic center of RdRp placed CHIMV on the genetic branch of the QYBV group. 9, 10 The amino acid sequence of this domain of CHIMV has an 87% identity with QYBV, Geran virus (GERV), and Bandia virus (BDAV), the other members of the QYBV group. 11À14 All these data are consistent with the fact that viruses of the QYBV group, as well as CHIMV, have an environmental connection to ticks of the Ornithodoros genus and to the burrows of rodents. QYBV has repeatedly been isolated from O. erraticus ticks, collected in burrows of the African grass rat (Arvicanthis niloticus) in the Nile valley and the Nile delta in Egypt. 13 To date, only short sequences of the RdRp of QYBV are available in GenBank, but recently we gave a genetic characterization of GERV, isolated in Transcaucasia and, apparently, closely related to QYBV. 11 The full-length amino acid comparison of CHIMV with GERV showed that their nucleocapsid proteins N (S-segment) have only a 55.6% identity. The similarity of complete amino acid sequences of RdRp (L-segment) is 74.8%. The similarity of the polyprotein precursor of Gn/Gc is 55.6%. The proteins of CHIMV have 30.3À42.4% aa (N-protein), 27.5À45.1% aa (Gn/Gc precursor), and 48.1À62.3% aa (RdRp) identities with their counterpart proteins in other nairoviruses. Among these nairoviruses, CHIMV has the highest level of similarity with ISKV, which is associated with bats in Central Asia (Figures 8.10À8.12) . 15 Arthropod Vectors. Most isolations of CHIMV were obtained from Ornithodoros tartakovskyi ticks. These ticks are common in the Irano-Turanian and mountain provinces of Asia (Kazakhstan, the central Asian republics, northeastern Iran, and China (Xinjiang)). The western border of the area in question is the eastern shore of the Caspian Sea (53À54 E), the eastern border is in Xinjiang (87 E) , and the northern border is 44À47 N. The typical biotopes that O. tartakovskyi ticks inhabit are the foothills of dry steppes with loess soils. The ticks also inhabit meadow steppes and deserts (floodplain terraces and canals). O. tartakovskyi ticks prefer burrows of small diameter (inhabited by rodents, including jerboas, ground squirrels, small predators, and hedgehogs, as well as by turtles and birds). Synanthropic biotopes are rarely inhabited. 16 Vertebrate Hosts. The great gerbil (family Muridae, subfamily Gerbillinae, genus Rhombomys) is distributed from the shores of the Caspian Sea on the plains of central Asia and southern Kazakhstan, to the deserts of central Asia, Iran, and Afghanistan, and on eastward to northern China and Inner Mongolia. Great gerbils are typical inhabitants of sandy deserts and form a colony with complex multistory burrows that have a large number of entranceways and egresses (up to 200À500). These burrows are a specific biotope that exists for many decades, and they maintain natural foci (in particular, of plague) in arid areas. 6, 8 Animal Infection. The significance of CHIMV in the pathology of humans is unknown. Antibodies to CHIMV have been found in camels (9.5%) in the Kashkadarya region in Uzbekistan. 5 This finding shows the ability of CHIMV to infect camels, as does QYBV, but additional studies are necessary to clarify the pathogenicity of CHIMV in humans and cattle. 17 

History. GRNV (strain LEIV-10899Az) was isolated from Ornithodoros verrucosus (family Argasidae, subfamily Ornithodorinae) ticks collected in a burrow of red-tailed gerbils (Meriones (Cricetidae) erythrurus) near Geran Station, Goranboy district, Azerbaijan; Figure 8 .15). Serological methods have failed to identify GRNV, but the virus has been sequenced and classified into the Nairovirus genus (family Bunyaviridae). 1 Taxonomy. The genome of GRNV was sequenced by a next-generation sequencing approach. 1 Full-length genome analysis revealed that the genetic similarity of GRNV to other known nairoviruses is, on average, 30À40% aa for the nucleocapsid protein (N, S-segment), 27À33% aa for the polyprotein precursor of the proteins Gn and Gc (M-segment), and 48.0À74.8% aa for RdRp (L-segment). The highest level of similarity all three proteins of GRNV have is to that of CHIMV (54.2À74.8% aa identity) and that of ISKV (42.4À62.3% aa identity). 2,3 Further analysis based on a comparison of partial sequences of the conservative core domain of RdRp of the nairoviruses showed that GRNV and CHIMV were most closely related to QYBV, which is the prototypical virus of the group of the same name. 4 The nucleotide sequence of the RdRp core domain of GRNV has 74.3% nt and 97.1% aa identities with the counterpart sequence of QYBV. The data obtained allow GRNV to be classified as a virus of the QYBV group (Figures 8.10À8.12). The phylogenetic relationship between GRNV and QYBV corresponds to their similar ecological characteristics. QYBV was first isolated in 1952 by R. Taylor and H. Dressler from argasid Ornithodoros erraticus ticks collected in a rodent burrow in the Nile River delta near Qalyub village, Egypt (30 N, 32 E). 5À7 Complementbinding antibodies to QYBV were found in humans (1.5%), camels, donkeys, pigs, buffalos, dogs, and rodents. 1, 7 The antigenic group of Qalyub, a group that includes QYBV and antigenic-related BDAV, is one of the prototypical groups of the Nairovirus genus. 5, 8 Previously, QYBV had been repeatedly isolated from O. erraticum collected in the burrows of rodents (Arvicanthis) in Africa. The second member of the QYBV group, BDAV, was isolated from O. sonari (a member of the O. erraticus group) collected in the burrows of rodents (mainly Mastomys) in Senegal. 9, 10 The isolation of GERV, which is closely related to QYBV, is the first confirmation of the circulation of QYBV group viruses in Transcaucasia.

Arthropod Vectors. The area of distribution of O. verrucosus ticks covers the southern part of Moldova as well as Ukraine and the Caucasus region, and is limited by 47 30 0 N latitude. The area includes the southern part of Russia (the Krasnodar and Stavropol regions), the northern and eastern foothills of Dagestan, the foothills and lowland hills of Georgia, the valleys of the Hrazdan River in Armenia, the foothills of the Lesser Caucasus Mountains in Azerbaijan, and the Gobustan Plateau and the Absheron Peninsula, also in Azerbaijan.

O. verrucosus ticks inhabit shelter biotopesin particular, the burrows of red-tailed gerbils (Meriones (Cricetidae) erythrurus), animals that are common in central Asia, southern Kazakhstan, and eastern Transcaucasia. Redtailed gerbils tends to inhabit desert and semidesert landscapes. Their burrows are deep and may have 5À10 entranceways and egresses.

History. ISKV (prototypic strain, LEIV-315K) was originally isolated from a pool of internal organs (liver, spleen, brain) of Nyctalus noctula bats, and their ticks (Argas (Carios) vespertilionis) were collected near Issyk-Kul Lake in Kyrgyzstan in 1970 (Figure 8 .16). 1, 2 Subsequently, ISKV was isolated from other bat species of the Vespertionidae family (Vespertilio serotinus, Vespertilio pipistrellus, Myotis blythii, Rhinolophus ferrumequinum), and from birds, in different regions of Kyrgyzstan and Tajikistan. 3À11 Two strains were isolated from Anopheles hyrcanus mosquitoes and Culicoides schultzei biting midges, respectively (Figure 8.16, Table 8 .10). 3, 12, 13 Complement-fixation testing showed that ISKV is closely related or identical to the Keterah virus, which was isolated from Scotophilus temminckii bats and A. pusillus ticks in Malaysia in 1960. 14, 15 A strain that has a close, one-sided antigenic relationship to ISKV, LEIV-218Taj (named Garm virus), was isolated from a common redstart (Phoenicurus phoenicurus) caught in the village of Garm, Tajikistan, Morphological studies by electron microscopy characterized ISKV as a member of the Bunyaviridae family, and because no antigenic relation to any known viruses was found, it was assigned to the unclassified bunyaviruses. 16 Taxonomy. The genome of the prototypical strain of ISKV, LEIV-315K, was sequenced, and, on the basis of sequence analysis, the virus was classified into the Nairovirus genus. 17 Like the genomes of other nairoviruses, that of ISKV consists of three segments of RNA (in negative polarity), each of which has a single ORF-encoded nucleocapsid protein (N, 485 aa, S-segment), a polyprotein precursor of the envelope glycoproteins Gn and Gc (1,631 aa, M-segment), and a RdRp (3,950 aa, L-segment). A pairwise comparison of the full-length nucleotide and deduced amino acid sequences of the ISKV ORFs with those of other nairoviruses revealed 48.2À51.1% nt (39.0À42.1% aa), 37.3À39.7% nt (23.2À26.5% aa), and 43.1À47.0% nt (31.9À34.5% aa) identity for RdRp, the precursor of Gn and Gc, and the N protein, respectively (Table 8.10) .

Phylogenetic analysis carried out for the fulllength amino acid sequences by the maximumlikelihood nearest-neighbor method showed that ISKV occupies a new and distinct branch on the phylogenetic trees relevant to all three nairovirus proteins (RdRp, Gn/Gc, and N) (Figures 8.10À8.12) .

For the many known nairoviruses (i.e., QYBV, DGKV, and HUGV, as well as for a new nairovirus that was found in European bats by a metagenomics approach), there are only partial sequences of the conservative catalytic core domain of RdRp. 16, 18, 19 The level of identity for this domain of ISKV with other nairoviruses ranged from 59.6À66.1% for the nucleotide sequence and 64.8À75.2% for the amino acid sequence (Table 8 .10). The ISKV RdRp core domain has the highest level of identity with QYBV (66.6% nt and 74.5% aa). The phylogenetic tree constructed on the basis of the amino acid alignment of the RdRp core domain of nairoviruses confirms the topology of ISKV on a new genetic branch of the nairoviruses (Figures 8.10À8.12) .

Arthropod Vectors. Most isolates of ISKV were obtained from Argas vespertilionis ticks, and we can assume that these ticks are the main natural reservoir of the virus. The range of ticks of the A. vespertilionis group covers territory in central Asia, Africa, Oceania, and Australia ( Figure 8.17) .

Vertebrate Hosts. The natural vertebrate hosts of ISKV are apparently bats-specifically, the genera Nyctalus, Vespertilio, Rhinolophus, and Myotis (family Vespertilionidae). These bats are common in the temperate and subtropical zones of Europe, Asia, and North Africa, and widespread ISKV transmission and the appearance of an emergency are possible in all of their territories.

Human Pathology. The first case of Issyk-Kul fever was registered in Tajikistan in August 1975 when a staff member became ill after catching bats during surveillance for arbovirus. ISKV was isolated from his blood on the second 21 The disease occurs with fever (39À40 C), headache (94%), dizziness (50%), hyperemia of the throat (48%), cough (25%), and nausea (31%). The outcome is generally favorable, and no deaths have been registered. 18 Most of the cases were associated with the presence of bats in the attic of the residence. The primary route of human infection was apparently by argasid ticks, but respiratory or alimentary routes (via the feces and urine of bats) could not be excluded. Furthermore, a laboratory experiment showed that ISKV can be transmitted by Aedes caspius mosquitoes. 22 The percentage of the population immune to ISKV in the southern part of Tajikistan is 7.8%. In Kyrgyzstan, antibodies to ISKV have been found in 0.7À3.2% of the human population.

The highest percentage (9%) with antibodies to ISKV was found in the southeastern part of Turkmenistan. 12 

History. Uzun-Agach virus (UZAV), strain LEIV-Kaz155, was isolated from the liver of a Myotis blythii oxygnathus (order Chiroptera, family Vespertilionidae) bat caught in the vicinity of the village of Uzun-Agach, Alma-Ata district, Kazakhstan, during the virological sounding of territory in central Asia and Kazakhstan in 1977 (Figure 8.18 ). 1À3 On the basis of virion morphology, UZAV was classified into the Bunyaviridae family. No serological study of UZAV was ever conducted, but the place of UZAV isolation, Uzun-Agach, is close to where ISKV was originally isolated, namely, near Issyk-Kul Lake, and the source of both viruses is the same: bats. 4, 5 Taxonomy. The full-length genome of UZAV was sequenced, and, on the basis of phylogenetic analysis, the virus was classified into the Nairovirus genus. 6 The genome of UZAV, like those of other nairoviruses, consists of three segments of ssRNA with negative polarity. The L-segment encodes RdRp (3,988 aa), the M-segment encodes a polyprotein precursor of the envelope glycoprotein Gn and Gc (1,621 aa), and the S-segment encodes the nucleocapsid protein N (485 aa). A pairwise comparison of the sequence of the UZAV genome with those of other nairoviruses showed that the virus is related most closely to ISKV. Full-length sequences of the L-and M-segments of UZAV have, respectively, 69.3% nt and 64.1% nt identities with those of ISKV. Amino acid sequences of RdRp (S-segment) of UZAV and ISKV have 76.2% aa similarity. The similarity of the amino acid sequences of the precursor of Gn and Gc for UZAV and ISKV is 66.7% aa. A comparison of the S-segments of UZAV and ISKV revealed that they are almost identical (99.6%). Thus, we can conclude that UZAV is a reassortant virus that got an S-segment from ISKV. Phylogenetic analysis based on L-and M-segments placed UZAV in the lineage of ISKV (Figures 8.10À8 .12). 6, 7 Vertebrate Hosts. The vertebrate host of UZAV is apparently bats, but because only a single isolation was obtained, this assertion is speculative. The finding that UZAV is a reassortant virus closely related to ISKV suggests that UZAV occupies the same ecological niche as ISKV and therefore is associated with bats and their argasid ticks. Myotis blythii oxygnathus, the bat from which UZAV was isolated, is common in the southern parts of the Russian Plain and in western Siberia, Caucasia, Kazakhstan, southern Europe, northern Africa, Middle and Central Asia, Iran, and Iraq. Bats are important natural reservoir of emerging viruses. 8À11 ISKV and UZAV are the first nairoviruses that appear to be associated with bats.

Sakhalin virus (SAKV) has been isolated from Ixodes (Ceratixodes) uriae (family Ixodidae, subfamily Ixodinae) ticks, which are obligate parasites of auks (family Alcidae). The prototypical strain of SAKV (LEIV-71C) was isolated in 1969 from I. uriae ticks collected in a colony of the common murre (Uria aalge) on Tyuleniy Island near the southeastern coast of Sakhalin Island in the Sea of Okhotsk (48 29 0 N, 144 38 0 E; Figure 8 .19). 1À4 Subsequently, 52 strains of SAKV were isolated from I. uriae ticks on Tyuleniy Island and Iona Island in the Sea of Okhotsk, the Commander Islands in the Barents Sea, and the southeastern coast of the Chukotka Peninsula in the Bering Strait (Table 8 .11). 4À7 On the basis of virion morphology, SAKV has been classified into the Bunyaviridae family. SAKV was the first of the eponymous viruses, which together have formed a basis for the Nairovirus genus. 8 Paramushir virus (PMRV), prototypical strain, LEIV-2268, a virus of the SAKV group, was originally isolated from Ixodes signatus ticks collected in 1972 in a colony of cormorants (Phalacrocorax pelagicus) on Paramushir Island (in the Kuril Islands) (50 23 0 N, 155 41 0 E; Figure 8 .19). 9,10 Later (in 1972À1987), 18 strains of PMRV were isolated from I. uriae ticks, collected in the nests of auks (family Alcidae) on Tyuleniy Island in the Sea of Okhotsk and on the Commander Islands in the Bering Sea (Table 8 .11). 11À14 At least five nairoviruses are included in the SAKV group. 3,10,15À17 Avalon virus (AVAV), which was isolated from engorged imagoes and nymphs of I. uriae collected in L. argentatus nests on Great Island, Newfoundland, , in 1972, is apparently identical to PMRV. 15, 18 Several strains of AVAV were isolated in 1979 in Cap Sizun, Brittany, France. 19 Clo Mor virus (CMV) was isolated in 1973 from nymphal I. uriae ticks collected in a Uria aalge colony of Clo Mor, Cape Wrath, Scotland. 20 CMV was found to be closely related to SAKV in a complementfixation test. Two strains of CMV were isolated from I. uriae collected in seabird colonies on Lundy Island (England) and the Shiant Isles (Scotland) ( Table 8.12) . 18, 20 Rukutama virus (RUKV) (strain LEIV-6269S), which previously had been included in the SAKV group, is now classified into the Uukuniemi virus (UUKV) group in the Phlebovirus genus. 9, 21 Taxonomy. Complete genomes of SAKV (strain LEIV-71C) and PMRV (LEIV-1149K) were sequenced. 9 Also, partial sequences of RdRp of Tillamook virus (TILLV, identical to SAKV), isolated from I. uriae ticks on the Pacific coast (Oregon) of the United States, are available (Table 8 .12). 18 A full-length genome comparison showed that SAKH and PMRV respectively share 75.6% nt and 88.0% aa identities in RdRp (L-segment), 59.7% nt and 57.9% aa in the precursor of Gn and Gc (M-segment), and 62.3% nt and 62.2% aa in the nucleocapsid protein (S-segment). SAKV N-protein ranges from 30% (CASV, HUGV) to 43% (CCHFV) similarity to other nairoviruses. The similarity of RdRp and the precursor of Gn and Gc proteins of SAKV to other nairoviruses ranges from 42.8% (CASV, HUGV) to 50.8% (CCHFV), respectively, and from 25.9% (ERVEV, TFAV) to 28.9% (NSDV, DUGV), respectively. 9 Arthropod Vectors. It has been shown that the infection rate of infected Ixodes uriae imagoes is 2 times higher than of the species' nymphs and 10 times higher than that of the larval stage. Transovarial transfer of SAKV has been found to be 10%. The infection rates of male and female ticks are approximately the same. The hypostome of male I. uriae ticks is vestigial; therefore, they cannot be infected by breeding on infected birds. The infection rate of I. uriae imagoes is at least 20 times higher than that of I. signatus imagoes. 4À6,22,23 Some other species of Ixodes ticks are parasites of seabirds and may be an additional reservoir of SAKV. I. auritulus and I. zealandicus ticks are distributed from Alaska to Cape Horn in South and North America. 24 Laboratory experiments have demonstrated that Aedes aegypti and Culex pipiens molestus mosquitoes can be infected by SAKV as they suck blood. The virus was found in mosquitoes on 9, 14, and 19 days after infection in titers 1.0, 1.5, and 2.0 log 10 (LD 50 )/10 μL, respectively. However, it was shown that infected mosquitoes could not transmit the virus to mice through a bite. 6, 22 Vertebrate Hosts. Ixodes uriae ticks and their host, the common murre (Uria aalge), are a natural reservoir of SAKV. Pelagic cormorants (Phalacrocorax pelagicus) and their obligate parasites (I. signatus) likely have only an additional influence. Antibodies to SAKV have been found in the common murre (U. aalge), pelagic cormorants (P. pelagicus), fulmars (Fulmarus glacialis), tufted puffins (Lunda cirrhata), and black-legged kittiwakes (Rissa tridactyla) in the Far East. 4À6,22 A serological examination of birds via an indirect complement-fixation test revealed that the northern boundary of the range of SAKV is the Commander Islands, where antibodies have been found in 2.2% of birds. The southernmost place where antibodies have been detected (1.1% birds) is Kunashir Island in the Kuril Islands. Antibodies were found most often (in 4.1À17.8% of birds) in the central part of the basin of the Sea of Okhotsk (on Sakhalin Island, Tyuleniy Island, and Iona Island). Antibodies were also found in the red-necked phalarope (Phalaropus lobatus), sanderling (Calidris alba), the long-toed stint (C. subminuta) (up to 8.4% of the population), fulmars (F. glacialis) (4.9%), Leach's petrels (Oceanodroma leucorhoa), tufted puffins (L. cirrhata) (4.6%), the common murre (U. aalge) (3.8%), Japanese 5, 6, 22 Neutralizing antibodies to AVAV, a virus closely related to PMRV, have been found in 27.6% of puffins (Fratercula arctica), petrels (Calonectris leucomelas), and herring gulls (Larus argentatus) in Canada. 24, 25 Findings of antibodies to SAKV in seabirds carrying out their annual seasonal migration to the Southern Hemisphere suggest the possibility of transcontinental transfer of the virus to the Southern Hemisphere. The closely related Taggert virus (TAGV) was isolated from Ixodes uriae ticks in penguin colonies on Macquarie Island, a phenomenon that may indicate a transfer of viruses by birds and their ticks between the Northern and Southern Hemispheres.

Human Infection. Three human cases of cervical adenopathy associated with AVAV were described in France. 25 Serological examination of farmers in Cap Sizun, Brittany, France, found only 1% of the population positive. 18 

History. TAMV (prototypal strain, LEIV-1308Uz) was originally isolated from Hyalomma asiaticum asiaticum (family Ixodidae, subfamily Hyalomminae) ticks collected from sheep in the arid landscape near the town of Tamdybulak Subsequently 52 strains of TAMV were  isolated in Uzbekistan, 4À7 Turkmenistan, 8À11  Kyrgyzstan, 12,13 Kazakhstan, 11, 14, 15 Armenia, 6, 16 and Azerbaijan 8,17À19 in 1971À1983 (Table 8.13) . Most of the strains were obtained from H. asiaticum ticks, but several were isolated from birds, mammalians (including bats), and sick humans. On the basis of virion morphology, TAMV has been classified into the Bunyaviridae family. Serological studies by complement-fixation and neutralization tests revealed no antigenic relationships of TAMV with any known viruses. 2 Taxonomy. Three strains of TAMV isolated in Uzbekistan (LEIV-1308Uz), Armenia (LEIV-6158Ar), and Azerbaijan (LEIV-10226Az) were completely sequenced. 20 Phylogenetic analysis of the full-length sequences showed that TAMV is a novel member of the Nairovirus genus, forming a distinct phylogenetic lineage (Figures 8.10À8.12 ). The similarity of the amino acid sequence of TAMV RdRp (L-segment) with those of other nairoviruses is 40% aa, on average. The similarity of the RdRp of TAMV with that of the nairoviruses associated predominantly with ixodid ticks (CCHFV, Hazara virus (HAZV), and DUGV) is higher (40% aa) than that with viruses associated with argasid ticks (ISKV and CASV) (38% aa). The similarity of the TAMV polyprotein precursor of Cn and Gc with that of other nairoviruses is less than 25% aa. The similarity of the amino acid sequence of the nucleocapsid protein (S-segment) of TAMV is 33% aa with ixodid nairoviruses and 28% aa with argasid nairoviruses. Phylogenetic analysis of the catalytic core domain of the RdRp of the nairoviruses confirms that TAMV forms a novel group in the Nairovirus genus (Figures 8.10À8.12 ). 20 Genetic diversity among the three sequenced strains of TAMV is low. The prototypic strain LEIV-1308Uz, isolated in central Asia, has 99% nt identity in the L-segment with LEIV-10226Az from Transcaucasia. The L-segment of the strain LEIV-6158Ar has 94.2% nt and 96.3% aa identity with the L-segment of LEIV-1308Uz. The similarity of the M-segment of LEIV-1308Uz with those of LEIV-10226Az and LEIV-6158Ar is 93% nt and 89% aa, respectively. The similarity of the S-segment among the three strains is 93À95% nt. 20 Arthropod Vectors. H. asiaticum ticks are apparently a main reservoir of TAMV. More than half (57%) of TAMV isolations were obtained from H. asiaticum asiaticum ticks, 6% from H. asiaticum, 8% from H. anatolicum, 6% from H. marginatum, 6% from Rhipicephalus turanicus, and 2% from Haemaphysalis concinna. The infection rates of male and female ticks in endemic territory were 1:210 and 1:200, respectively. The infection rate of H. asiaticum nymphs was 20 times lower. 7, 10, 14, 16 Furthermore, TAMV was isolated from larvae of H. asiaticum, which were hatched from eggs in the laboratory, indicating transovarial transmission of the virus. H. asiaticum asiaticum ticks are the most xerophilous subspecies of the Hyalomma genus (Ixodinae subfamily), 21 a characteristic that allows TAMV to be distributed over the Karakum desert in Turkmenistan, the Moinkum desert in Kazakhstan, and the central part of the Kyzyl Kum desert in Kazakhstan and Uzbekistan. 7 .

Animal Hosts. The larvae of H. asiaticum feed on ruminants, hoofed animals, small predators, hedgehogs, birds, and reptilians. One of the major hosts of H. asiaticum preimagoes is the great gerbil (Rhombomys opimus). Wild animals, as well as sheep and camels, are the hosts for H. asiaticum imagoes and may be involved in the circulation of TAMV (Table 8 .13).

Human Pathology. Sporadic cases of the disease associated with TAMV was registered in Kyrgyzstan in October 1973, when TAMV was isolated from the blood of a patient with fever (39 C), headache, arthralgia, and weakness. 16 H. asiaticum asiaticum ticks rarely attack humans, and no outbreaks of TAMV fever have been registered; however, human infection by H. asiaticum ticks is still possible concinna (Ixodidae, Haemaphysalinae) during 1971À1975. 1,2 According to preliminary information, BURV is not able to agglutinate erythrocytes of birds and mammals and has no antigenic relationships with 59 arboviruses from different groups of the Togaviridae, Taxonomy. The genome of BURV was sequenced, and the virus was classified into the Nairovirus genus, family Bunyaviridae. The genome consists of three segments: an L-segment (ORF, 11,919 nt; encodes RdRp); an M-segment (ORF, 4,035 nt; encodes a polyprotein precursor of the envelope proteins Gn and Gc); and an S-segment (ORF, 1,482 nt; encodes the nucleocapsid protein N). 3, 4 A comparison of RdRp sequences of BURV with those of other nairoviruses demonstrated that the virus is distantly related to TAMV (59% aa similarity). The similarity of the RdRp catalytic core domain of BURV to that of TAMV is 82% aa, compared with about 60% aa for viruses in other phylogenetic groups.

The level of similarity for the nucleotides sequences of this part of the RdRp of BURV is 68% nt with those of TAMV and 45À50% nt with those of other viruses (Figure 8 .10). 3 The M-segment of BURV has a long ORF and encodes a polyprotein precursor of the envelope glycoproteins Gn and Gc. 4 The size of the polyprotein precursor is 1,344 aa. The mature Gn and Gc proteins of nairoviruses are formed by complex processes involving cellular peptidases. By the NetNGlyc 1.0 server, 11 potential glycosylation sites were predicted, with only 5 within mature Gn or Gc proteins. 5, 6 The level of similarity of the amino acid precursor of Gn and Gc in BURV is 45% with that of TAMV and no more than 27% with viruses of other phylogenetic groups. Phylogenetic analyses based on a comparison of the full-length polyprotein precursor demonstrated the position of BURV on the TAMV branch and was consistent with the RdRp data ( Figure 8 .11). 3 The S-segment of nairoviruses encodes a nucleocapsid protein (N). 4, 7 The size of the BURV nucleocapsid protein is 493 aa, corresponding to the average size of the N protein of other nairoviruses (480À500 aa). The level of similarity of the amino acid sequence of BURV N protein with that of TAMV is 44%, and that with the amino acid sequences of other nairoviruses is30À32%. Phylogenetic analyses of BURV N protein are represented in Figure 8 .12. The phylogenetic position of BURV is on the TAMV branch, despite the virus's having the lowest level of similarity of the N protein compared with that of other virus proteins.

Arthropod Vectors. As mentioned earlier, six strains of BURV were isolated from the ticks Haemaphysalis punctata (five strains) and

Haem. concinna (one strain) in 1971À1975. The rate of infected ticks was 2.2À2.6%. BURV is associated with Haem. punctata and Haem. concinna ticks in pasture biocenoses. The virus is phylogenetically close to TAMV, which is also associated with ixodes ticks in pasture and desert biocenoses. 8 

The Orthobunyavirus genome consist of three segments of single-stranded negative-sense RNA designated as large (L), medium (M), and small (S) (Figure 8 .22). 1 The L-segment of the prototypical BUNV (6,875 nt in length) encodes the viral RdRp. 2 The M-segment (4,458 nt) encodes two surface glycoproteins (Gn and Gc) and a nonstructural protein (NSm). 3, 4 The S-segment (961 nt) encodes the nucleocapsid protein (N) and a nonstructural protein (NSs). The NSs protein is considered a pathogenic factor for vertebrates, because it may act as an antagonist of interferon, which is involved in blocking the host's innate immune responses. 5À7 6, 7 to Olyka virus, isolated in 1973 from An. maculipennis mosquitoes collected in western Ukraine; 8À11 and to Chittoor virus, isolated in 1957 from An. barbirostris mosquitoes collected in Brahmanpally, Chittoor district, Andhra Pradesh state, India. 12 The African Ngari virus (NRIV) is reassortant between BATV and BUNV. 12, 13 In Russia, BATV was repeatedly isolated in different regions (Figure 8 .23).

Anadyr virus (ANADV), strain LEIV-13395, was isolated by S.D. Lvov from a pool of Aedes mosquitoes collected in September 1986 in a swamp tundra landscape near the village of Ukraine, and Russia are members of the European group. Two strains of BATV-LEIV-Ast04-2-315 and LEIV-Ast04-2-336-isolated in Russia were completely sequenced and placed into the cluster of the European strains. 14 Within this group, they are phylogenetically close to strain 42, isolated in the Volgograd region in 2003 from Anopheles messeae (maculipennis) mosquitoes, for which the partial nucleotide sequences of the L-and M-segments are known. Between the strains LEIV-Ast04-2-315 and LEIV-Ast04-2-336, there is very high level of nucleotide and amino acid identity of three segments of the genome: 99.6/99.0% (L-segment/RdRp), 99.9/100.0% (M-segment/ polyprotein predecessor), and 99.7/100.0% (S-segment/nucleocapsid). The levels of nucleotide identity of strain 42 with these strains on partial sequences of L-and M-segments are 98.6/98.8% and 100/100%, respectively; that is, for the M-segment, all available nucleotide polymorphisms are synonymous. The lowest observed genetic differences and the temporal and geographical proximities of the various strains of these viruses suggest a common origin as different isolates of the same strain of BATV circulating in the southern part of Russia.

Phylogenetic analysis of ANADV (strain LEIV-13395) revealed its similarity to BATV. The L-segment of ANADV is from 76.5% to 79.7% identical with those of the different BATV strains (Figure 8 .26, Table 8 .15). The identity of the L-segment of ANADV with the L-segments of other viruses of the Bunyamwera group is 73.5% (BUNV), 74.1% (CVV), and 73.9% (TENV). The amino acid and is about 82.5% with TENV and CVV. The amino acid similarity of the nucleocapside protein is 98.7% with that of BATV from Uganda.

Phylogenetic analysis of the nucleotide sequences of the S-, M-, and L-segments conducted with the use of a maximum-likelihood algorithm placed ANADV (LEIV-13395) on a distinct branch of the dendrogram that considers it a new representative of the Bunyamwera group.

Arthropod Vectors. BATV has been reported in Sudan, Africa. 15 The distribution of BATV in southeastern Asia includes Malaysia, India, Sri Lanka, Thailand, Cambodia, and Japan, 5,16 while in Europe BATV is distributed over Austria, Germany, Yugoslavia, Moldova, Ukraine, Belarus, and other countries. 2,17À19 In central Europe, BATV was isolated from Anopheles claviger, An. maculipennis (An. messeae), Coquillettidia richiardii, Aedes (Ochlerotatus) punctor, and Ae. communis. 6, 7, 20 A wide distribution of BATV in different landscape belts of the European part of Russia, as well as in Siberia and the Far East, was demonstrated: In the temperate belt the main source of BATV isolation was the zoophilic Anopheles genus, whereas in high latitudes (tundra, northern taiga) it was the Aedes genus. 18,21À24 In the European part of Russia, BATV has been isolated in the northern (Komi Republic), middle (Vologda region), and southern (Leningrad, Yaroslavl, and Vladimir regions; 2, 6, 17, 18, 20 In the southern hyperendemic regions of Russia, the main vector of BATV is An. messeae. According to our data, the infection rate of An. messeae in the middle belt of the Volga delta (Astrakhan region) reaches 0.188% (approximately 1 infected mosquito out of 500). Because this species of mosquito attacks mainly domestic animals, it serves as a biological barrier, reducing risk of infection to humas. In the northern areas (the subarctic, the northern taiga), BATV circulation is due mainly to Aedes mosquitoes: Ae. communis complex and Ae. punctor. Under experimental conditions, BATV was isolated from hibernating females of An. messeae. Hibernation is one of the mechanisms by which BATV survives during the winter. 20, 25 Vertebrate Hosts. In anthropogenic biocenoses of the southern regions of Russia, domestic animals are the main vertebrate reservoir, because they (especially cattle) are the main hosts for An. messeae. BATV-neutralizing antibodies were found in India among rodents (Mus cervicolor (55.2%), Rattus exulans (36.4%), Rattus rattus (19.5%), Bandicota indica (15.5%)) and bats (Cynopterus sphinx) (2.6%). 2, 5 This indicator is significantly higher in India among domestic animals: goats (41.8%), camels (100%), cows (60.9%), and buffalos (23.3%). In Finland, anti-BATV antibodies occasionally were found among cows (0.9%), but not among reindeers. 19 The Chittoor strain is associated with mild illness, but is pathogenic to sheep and goats. 12 BATV was isolated from birds: crows (Corvus corone), coots (Fulica atra), and grey partridges (Perdix perdix). 9 Persistent avian infection was established experimentally with reactivation of viremia by cortisone six months after the acute infection period. 10 An investigation of 5,000 sera of domestic animals in Russia during 1982À1992 revealed anti-BATV antibodies among these animals significantly more often than among people (Table 8 .16). The largest immune layer was found in populations of horses (up to 80%), cattle (35À60%), sheep (up to 80%), and camels in forestÀsteppe, semidesert, and desert landscape belts. In contrast to the situation in Finland, antibodies were found in reindeer sera in a tundra landscape belt of the Chukotka Peninsula. No examinations of vertebrates in natural biocenoses were conducted.

Epidemiology. Epidemic outbreaks and sporadic cases caused by BATV, as well as outbreaks of hemorrhagic infection caused by Ngari virus, have been reported. 13, 15, 18, 26, 27 To date, no cases of laboratory infection are known. According to a serological examination of 10,000 people in the endemic regions of Russia, about 3À10% withstand BATV infection in an asymptomatic form. The highest infection rate was established in forestÀsteppe and steppe belts. (However, as a rule, the rate is higher for domestic animals than humans.) Some northern areas in Russia became hyperendemic for no apparent reason. 18, 21, 22 Pathogenesis. No pathogenetic mechanism during BATV infection in humans has yet been described in detail. There are experimental data, however, on BATV infection in primates: 28 Green monkeys (Chlorocebus sabaeus) were found to be carriers of the virus 50 days after inoculation (the observation period); the virus was pantropic, destroying small vessels and producing vasculitis and perivascular focal lymphohistiocytic infiltrates. Clinical Features. The disease etiologically linked with BATV proceeds mainly as influenzalike disease complicated by meningitis, malaise, myalgia, and anorexia. 13, 15, 18, 26, 27 At the same time, Ngari virus (reassortant between BATV and BUNV) infection in east Africa appears as outbreaks of hemorrhagic fever. 13 Diseases associated withtheclosely related ILEV in Africa and Madagascar also proceed with hemorrhagic phenomena and with lethal outcomes. 29, 30 Diagnostics. A highly specific test based on RT-PCR has been developed, as have ELISA tests for the detection of specific anti-BATV IgM and IgG. 24 Genome and Taxonomy. The genome of the CE group of viruses consists of three segments of ssRNA with negative polarity. The L-segment of LACV, a prototypical virus of the group, is 6,980 nt in length, the M-and S-segments 4,527 and 984 nt, respectively. As in other bunyaviruses, the L-segment encodes RdRp, the M-segment a polyprotein precursor of the envelope glycoproteins Gn and Gc, and the S-segment nucleocapsid protein (N). Two nonstructural proteins are found in infected cells: NSs, which encodes by adding an ORF in the S-segment; and NSm, which forms during the maturation of the Gn and Gc proteins from the precursor. 11 25, 26 but viruses of the CE serocomplex were isolated from Ae. albopictus (a known vector for at least 22 arboviruses), which was imported from southeastern Asia and spread into 30 states of the United States. 27, 28 Transovarial transmission was established in Ae. vexans 29 and Cs. annulata. 16 Overwintering of TAHV was documented in Cx. modestus and Cs. Annulata females. 16 Mosquito species have been defined and classified only partially in connection with the huge volume of this laborious work. The majority of strains were isolated from pools of mosquitoes belonging to different species. Of 250 strains that were isolated (1 strain was isolated from a wild population of the common house mouse, Mus musculus), only 112 were isolated from strictly defined species (Table 8 .18). The other 138 strains were isolated from Aedes mosquitoes of unidentified species: 34% of strains were from Ae. communis, 18% from the mixed pools, in which Ae. communis prevailed. Strains were isolated from other species significantly less often. Only one strain was isolated from Anopheles maculipennis (An. messeae) and Culiseta alaskaensis. 30 The dynamics of the seasonal infection rate of mosquitoes was investigated for two years on the model of the northern part of the Russian Plain and the eastern part of Fennoscandia. In tundra, the epizootic period begins with the second decade of July and proceeds to the beginning of August, when the activity of mosquitoes comes to an end. In forest tundra, the epizootic period begins with the first decade of July and proceeds for 1.5 months; in the northern taiga, this period lasts at least 2 months (JulyÀAugust); in the middle and southern taiga, the first strains began to be isolated in the second decade of June. The mosquito infection rate increases significantly in the third decade of July and reaches a maximum in the middle to end of August, when the total number of mosquitoes decreases. 30, 31 The data collected testify to an almost universal distribution of CE serocomplex viruses in all landscape belts, except the Arctic, in all six physicogeographical lands examined in the north of Russia, 32 located on a territory of more than 10 million km 2 .

The infection rate of mosquitoes increases (р , 0.01) in moving from the subarctic (tundra) (0.0090 6 0.0018%) to the landscape belt of the middle taiga (0.0196 6 0.0020%).

This indicator in tundra and in the forest tundra is close to that in the southern taiga of the Russian Plain (0.0122%), in North America (0.01%), and in the forest steppes of the Russian Plain (0.0100À0.0017%). In the steppe belt of the Russian Plain, the infection rate of mosquitoes appeared to be the smallest (0.001%). In the leaf forests of the Russian Plain (0.0148%) and of the former Czechoslovakia (0.0210%), the infection rate of mosquitoes is comparable to that for landscape belts of the northern and middle taiga.

To date, at least s63 CE serocomplex virus strains were isolated from mosquitoes in the central and southern parts of the Russian Plain. Among them, 4 strains were isolated from the blood and spinal fluid of patients, and 3 strains from the internal parts of rodents (2 from the bank vole, Myodes glareolus; and 1 from the wood mouse, Apodemus sylvaticus). The infection rate of mosquitoes depends on the landscape belt and the particular season in which field material was collected. The rate decreases, as a rule, from the north to the south. Data indicating an absence of viruses in semideserts can be explained by an insufficient quantity of mosquitoes collected, but in wet subtropical zones in Azerbaijan CE serocomplex viruses were isolated from Anopheles hyrcanus. 33 In the southern taiga belt and mixed forests, the infection rate of mosquitoes was defined to be from the third week of May to the second week of August and two peaks were noted: at the end of June (the emergence of the first generation of Aedes mosquitoes) and at the end of July to the beginning of August (the emergence of the second generation of Aedes mosquitoes). In the majority of the southern belts, the infection rate was registered from the second week of June until the end of August with a small peak in the first week of August caused by the emergence of the second generation of Aedes mosquitoes and by the peak of activity of Culex, Coquillettidia, and Anopheles mosquitoes. 17 In steppe and forestÀsteppe belts, CE serocomplex viruses were isolated from mosquitoes collected in the Rostov and Orenburg regions, as well as in the foothills of the Caucasus Mountains (Krasnodar Krai). Most of the strains were obtained from Aedes mosquitoes, which play the leading role in virus circulation. In these regions, Anopheles mosquitoes join the virus population maintenance (three strains were isolated), being ecologically connected with agricultural animals and, because of that connection, playing an important role as an indicator species in anthropogenic biocenoses. In the center and south of the Russian Plain, there is a mix of populations of INKV, TAHV, KHTV. 31, 32 Vertebrate Hosts. The principal vertebrate hosts of TAHV in Europe are Lagomorpha (hares (Lepus europaeus), rabbits (Oryctolagus cuniculus), hedgehogs (Erinaceus roumanicus), and rodents (Rodentia)). Experimental viremia has been established in lagomorphs, hedgehogs, ground squirrels (Citellus citellus), muskrats (Ondatra zibethicus), squirrels (Sciurus vulgaris), martens (Martes foina), polecats (Putorius eversmanni), foxes (Vulpes vulpes), badgers (Meles meles), bats (Vespertilio murinus), piglets, and puppies. 14, 15, 34, 35 In total, 251 strains of CE serocomplex viruses were isolated within all landscape belts of all physicogeographical lands (Figure 8 .30, Table 8 . 19 ). According to our data, the susceptibility of mosquitoes increased from the tundra to the northern and middle taiga; however, the highest indicators were noted to be in the forestÀsteppe and the steppe of western Siberia (in Altai Krai). Identification of these strains revealed at least three viruses of the CE complex: 2 strains of TAHV, 44 of INKV, and 183 strains of KHTV. 30 In all landscape belts east of the Yenisei River (central and northeast Siberia and the physicogeographical lands bordering the North Pacific Ocean), only KHTV strains have been isolated. West of the Yenisei River, INKV strains predominated in the tundra and the forestÀtundra of western Siberia, whereas KHTV prevailed in other landscapes located to the south. In the eastern part of Fennoscandia and in the north of the Russian Plain, INKV and KHTV strains were isolated in about equal proportions. 30 The pattern of distribution of TAHV, INKV, and KHTV over Northern Eurasia suggests that the emergence of the ancestor of CE serocomplex viruses probably is connected to Oligocene ChineseÀManchurian fauna of the deciduous forests of eastern Siberia evolving into Okhotsk fauna during the Upper Tertiary period. The Okhotsk fauna, in its turn, extended in early glacial times to the north, the west, and partially to the east in tundra through ancient Beringia and on into North America. The ancestral virus could then penetrate into North America together with this fauna and gradually extend in the southern direction, in the process laying the foundation for the appearance of some other viruses of the CE serocomplex now circulating mainly in North America. Mercurator, nigripes, excrucians 1 0.9

Maculipennis b 1 0.9

Total 112 100 a One strain was isolated from the genus Culiseta. b One strain was isolated from the genus Anopheles.

The introduction of the virus population to the Western Hemisphere probably occurred through two pathways around the Central Siberian Plateau: (i) through the tundra lying to the north of the plateau and (ii) through southern taiga and forestÀsteppe territories. These pathways can explain the modern predominance of KHTV in the forestÀsteppe belt of Siberia and in a taiga belt west of the Yenisei River. In moving to other ecological systems further to the west, KHTV could have been transformed partially to INKV and TAHV. The INKV population penetrated into the western part of the Eurasian subarctic through the taiga belt and occupied that part of Eurasia, whereas TAHV proceeded into the deciduous forests of Europe, where it now prevails. 36 Epidemiology. CEV is endemic in the United States in California, New Mexico, Texas, the southwestern part of Virginia, Tennessee, and Kentucky. 26, 37 Sporadic morbidity with CNS lesions occurs in those states, but the main morbidity is linked to LACV, which is endemic in 20 states, predominantly the U.S. Census BureauÀdefined East North Central states (Ohio, Wisconsin, Minnesota, Iowa, and Indiana), where morbidity reaches 0.1À0.4%. 26 Cases of LACV-associated encephalitis are within the distribution of the main vector-Aedes triseriatus-eastward from the Rocky Mountains. 38 During the last few decades, natural foci in West Virginia, North Carolina, and Tennessee, with sporadic cases occurring in Louisiana, Alabama, Georgia, and Florida, joined with previously known ones in Wisconsin, Illinois, Minnesota, Indiana, and Ohio. Thus, having traversed the distance from southeastern Asia to North America, Ae. triseriatus is now part of the North American virus circulation. 39 The clinical picture varies from an acute fever syndrome (in some cases with pharyngitis and other symptoms of acute respiratory disease) to encephalitis. Lethality is about 0.05%. From 40 to 100 cases occur annually. Generally, the virus attacks children age 10 and under (60%), a phenomenon that may be explained by the existence of a layer of immunity in up to 40% of adults. 40 JCV (in the United States and Canada) and SSHV (in the northern part of the United States and in Canada) are associated with sporadic cases of fever and encephalitis. 26 Domestic dogs are susceptible to LACV, which provokes encephalitis. 21, 34, 41, 42 The role of deer in virus circulation has been established as well. Horizontal and vertical transmission of viruses provides an active circulation of the virus, a high rate of infection in mosquitoes, and stability of natural foci under the relatively rough conditions of the central and northern parts of the temperate climatic belt. 43 All three viruses (INKV, KHTV, and TAHV) of the CE serocomplex distributed in Eurasia have significance in human pathology. 43, 44 These viruses were found in Czechoslovakia in 1959, 4, 45 Austria in 1966, 13 Finland in 1969, 6, 46 Romania in 1974, 12 Norway in 1978, 24 the former USSR(in Transcaucasia) in 1972, 47 and elsewhere in the European and Asian parts of Russia. 9,30,32,33,36,44,48À50 In Europe, human disease associated with TAHV presents as an influenzalike illness mainly in children with sudden-onset fever, headache, malaise, conjunctivitis, pharingitis, myalgia, nausea, gastrointestinal symptoms, anorexia, and (seldom) meningitis and other signs of CNS lesions. 16,42,51À56 The circulation of CE serocomplex viruses was established in China, 57 where they provoke human diseases with encephalitis 58 as well as acute respiratory disease, pneumonia, and acute arthritis. 59 In North America (the United States and Canada), LACV is the most important of these viruses, 60 but SSHV also is associated with human disease. 61 Between 1963 and 1981 in the United States, 1,348 cases of CE were reported. 60, 62 So, CE serocomplex viruses have circumpolar distribution. In Russia, these viruses are found from subarctic to desert climes ( Figure 8 .30, Table 8 .18). 32, 44 According to our summary data for 8,732 sera, the number of people with specific antibodies to CE serocomplex viruses in the tundra and forestÀtundra belts (27.8%) is significantly lower than the number in the north and middle taiga belts (48% and 47%, respectively). These data correlate with the infection rate of mosquitoes in those landscape belts. 31, 49 Results obtained from serological investigation of the human population correlate with those obtained from virological investigation of the mosquitoes (Figure 8 .31). The maximum immune layer of the healthy population is registered in the southern taiga. In the landscape and geographical zones located south of that landscape, a gradual decrease in this indicator takes place. Specific antibodies to INKV are seen everywhere that this virus circulates. In forest-Àsteppes, specific antibodies to TAHV and INKV are marked out with an identical frequency. In semideserts, anti-TAHV antibodies are found twice as often as anti-INKV ones. The small number of strains isolated in these natural zones precludes establishing a relationship between the circulation of viruses and an immune layer of the population. Active circulation of CE serocomplex viruses on the territory of Russia results in regular registration of the diseases caused by these viruses. More than 7% of all seasonal fevers are etiologically linked to such viruses, and in some natural zones (the southern taiga and the mixed forests), this indicator increases to 10À12%.

In mixed forests, the main etiological role most often belongs to INKV (50.4%), and in semideserts (Astrakhan region) to TAHV (76.5%). The diseases caused by CE serocomplex viruses in the center and south of the Russian Plain start appearing during the middle of May and reach a maximum in Almost equal titers of specific antibodies to more than one virus were revealed in 65 patients (35.5%) in a neutralization test. 31, 43, 49 Diseases were registered from May to September: in May, 22 cases (12.02%); in June, 35 (19.13%); in July, 67 (36.61%); in August, 54 (29.51%); and in September, 5 (2.73%). The seasonal dynamics in all landscape zones were identical: The maximum number of diseases is noted in JulyÀAugust. Diseases were registered everywhere in the form of sporadic cases and small outbreaks, but more often in the taiga and the deciduous forests of the European part of Russia and western Siberia. Most patients were 15À40 years old, with those up to 30 years making up 52.5% of all people infected. 9 Pathogenesis. A systematic destruction of small vessels, together with the development of vasculitis and perivascular focal lymphohistiocytic infiltrates, underlies the pathogenesis of the diseases caused by CE serocomplex viruses. Lesions in the lungs, brain, liver, and kidneys are the most frequent complications. 31, 49 Clinical Features. The incubation period lasts from 7 to 14 days, but in some cases is only 3 days. Three main forms of disease linked with CE serocomplex viruses have been proposed: (i) influenzalike; (ii) with primary compromise of the bronchiopulmonary system; (iii) neuroinfectious, which proceeds with a syndrome of serous meningitis and encephalomeningitis.

Analysis of the clinical picture of cases examined showed that 79.8% of cases proceeded without signs of CNS lesion, 20.2% with a syndrome of acute neuroinfection, and 8.9% with radiologically uncovered signs of changes in the bronchiÀlung system. A comparison of clinical forms and etiologic agents showed that INKV and TAHV often cause disease without CNS lesions (65.6% and 92.5%, respectively) and that INKV plays the leading role in acute neuroinfection (34.4%). The etiological role of KHTV was established in 14 cases without CNS symptoms of lesions. 63 Eighty-three patients had an influenzalike form of the disease etiologically linked to CE serocomplex viruses. The incubation period was 7À14 days. The disease began abruptly, with a high temperature that reached a maximum of 39À40 C in 98.9% of patients on the first day. The duration of the fever was 4.48 6 0.30 days. One of the main symptoms was an intensive headache (3.62 6 0.26 days in duration) that developed in the first few hours and was often accompanied by dizziness, nausea (31.3%), and vomiting (21.7%). 43,63À66 A survey of patients revealed infection of the sclera (59.0 6 3.4%), hyperemia of the face and the neck (10.8 6 3.4%), and, in some cases (3.6%), a spotty and papular rash on the skin of the trunk and the extremities. Violations of the upper respiratory airways were characterized by hyperemia of the mucous membranes of the fauces (95.2 6 2.3%)and congestion of the nose and a dry, short cough (13.2 6 3.7%). With regard to the lungs, 26.5 6 4.8% of patients exhibited rigid breathing a dry, rattling cough during auscultation, and a strengthening of the bronchovascular picture on roentgenograms. Among CNS symptoms, the most common were a decrease in appetite, a stomachache without accurate localization and with liquid stool, and a small increase in the size of the liver with a short-term increase in aminotransferase activity in the blood. Inflammatory changes in the bronchiÀlung system (bronchitis and pneumonia) occurred as well. In all cases in which it appeared, pneumonia had a focal character with full The etiological role of different CE serocomplex viruses has been established in 8% of 463 cases with acute diseases of the nervous system (serous meningitis, encephalomeningitis, arachnoiditis, acute encephalomyelitis, and seronegative tick-borne encephalitis (TBE)): INKV (56.7 6 8.1%), TAHV (8.1 6 4.5%), and unidentified (35.1 6 7.8%). The age of patients with CNS lesions was from 3 to 61 years, with the majority (51.5%) from age 21 to 30. Serous meningitis was observed in 29 patients who arrived at the hospital a mean 3.3 days after symptoms appeared. The disease began abruptly. The majority (58.6%) of patients complained of a high temperature that reached a maximum the first day, The duration of the fever was 4.54 6 0.05 days, with a critical (37.9%) or steplike (62.1%) decrease. Headache was noted in 100% of patients and was accompanied by dizziness in 31%. Vomiting developed on the first (53.6%) or the second (46.4%) day and continued in 67.7% of patients. Meningeal signs appeared in 96.5% of patients but were weak and dissociated in most cases, with only 37.9% of patients exhibiting rigidity of the occipital muscles. The duration of the meningeal signs was 3.50 6 0.4 days. The cells of the spinal fluid (investigated on the 4.57th 6 0.54 day of the disease) was lymphocytic, mostly reaching three digits and up to 500 cells (55.6%); the protein concentration was reduced (0.15 6 0.02 g/L) in 41.4% of cases but was within the normal range (0.31 6 0.01 g/L) in other cases. In 34.5% of patients exhibiting acute neuroinfection symptoms of bronchitis and focal pneumonia, their condition was confirmed radiologically.

Encephalomeningitis caused by INKV was characterized by an abrupt beginning and fast development of focal symptomatology (ataxy, horizontal nystagmus, and discoordination) against a background of common infectious and meningeal syndromes, including inflammatory changes to the spinal fluid. 43,63À66 The variability of the clinical picture of the diseases caused by CE serocomplex viruses and its similarity-especially at early stagesto that of other infections suggest the necessity of carrying out differential clinical diagnostics with a number of diseases. The influenzalike form needs to be differentiated, first of all, from influenza, especially in the presence of symptoms of neurotoxicity, as well as from other acute respiratory diseases (parainfluenza, adenoviral and respiratoryÀsyncytial diseases), pneumonia (including a mycoplasma and chlamydia etiology), and enteroviral diseases. The main epidemiological features and clinical symptoms that lend themselves to carrying out differential clinical diagnostics for the influenzalike diseases described here are presented in Table 8 .20. Note that considerable difficulties arise in implementing differential clinical diagnostics of the diseases that proceed with acute neuroinfection syndrome (serous meningitis, encephalomeningitis), especially when those diseases occur in the same season (Tables 8.20 and 8.21). 31, 44, 66 The main criteria in differential clinical diagnostics of the disease etiologically linked with CE serocomplex viruses are as follows (see Tables 8.20 and 8.21): acute onset; high short-term fever (4À8 days, on average) reaching a maximum on the first day and decreasing critically at the end of the feverish period; and intensive headache, nausea, vomiting, and weakness. Also observed are insignificant catarrhal phenomena (nose congestion, rare dry cough) or their complete absence. A radiograph of the chest reveals signs of bronchitis and focal pneumonia with poor clinical symptomatology. An examination of the liver shows that its size, as well as its aminotransferase activity, has increased. Changes in urine, such as albuminuria and, in some cases, cylindruria, are frequently reported. Finally, symptoms relating to the vegetative nervous system (hyperemia of the face and the neck, subconjunctival hemorrhage, bradycardia, and persistent tachycardia) can be observed, as can both CNS lesions in the form of serous meningitis and encephalomeningitis in combination with compromise of the bronciopulmonary system, liver, and kidneys.

Diagnostics. Specific diagnostics of the diseases etiologically linked with CE serocomplex viruses could be based on virological testing (using sensitive biological models of newborn mice or cell lines to isolate the strains) or on serological testing.

In the presence of the sera taken from patients during the acute period of the disease (the first 5À7 days) and in 2À3 weeks, the best method of retrospective inspection is a neutralization test. A hemagglutination inhibition test is considerably less sensitive. Both complement-binding reactions and diffuse precipitation in agar have no diagnostic value today. For serological reactions, it is necessary to utilize HKTV, TAHV, and INKV antigens simultaneously. (In reference labs, SSHV antigen should be used as well.) A quadruple (or greater) increase in the titers of specific antibodies or the detection of specific antibodies in the second serological test in their absence in the first test are diagnostic criteria. ELISA for IgG indication and monoclonal antibody capture ELISA (MAC-ELISA) for IgM indication provide good diagnostic opportunities.

Control and Prophylaxis. Supervision of morbidity and of the activity of natural foci linked with CE serocomplex viruses offers the following instructions: (i) Monitor the patient clinically and the disease epidemiologically.

(ii) Provide well-timed diagnostics and seroepidemiological investigations. (iii) Track the number and specific structure of mosquito vectors and possible vertebrate hosts.

History. Khurdun virus (KHURV), strain LEIV-Ast01-5 (deposition certificate N 992, 04.11.2004, in the Russian State Collection of Viruses), was isolated from a pool of internal parts of the coot (Fulica atra; order Gruiformes, family Rallidae), collected August 3, 2001 , in natural biomes in the western part of the Volga River delta, in Khurdun tract, Ikryaninsky District, Astrakhan region. 1 Later, nine more strains of KHURV were isolated from F. atra and the cormorant Phalacrocorax pygmaeus; order Pelecaniformes: family Phalacrocoracidae) in 2001À2004 (Figure 8 .32).

At least six viruses associated with birds have been shown to circulate in the Volga River estuary. 2,3 KHURV has not been identified by any serological method, 1 including sera against viruses of the Flaviviridae, Togaviridae, Bunyaviridae, and Orthomyxoviridae families. 4 Taxonomy. The genome of KHURV was sequenced, and phylogenetic analysis revealed that it is a new representative of the Orthobunyavirus genus (Figures 8.33À8.35). 5 The genome consists of three segments of ssRNA with negative polarity-an L-segment (6,604 nt), an M-segment (3,161 nt), and an S-segment (950 nt)-and has only 25À32% identity with those of other orthobunyaviruses. The terminal 3 0 -and 5 0 -sequences of KHURV genome segments, determined by rapid amplification of cDNA ends, are canonical for the orthobunyavirus (3 0 -UCAUCACAUG and CGTGTGATGA-5 0 ). 6 The L-segment of KHURV has a single ORF (6,526 nt) that encodes RdRp (2,174 aa). The similarity of KHURV RdRp with those of the orthobunyaviruses is 32%, on average. The similarity of the conservative polymerase domain III (A, В, C, D, and E motifs) 7 in RdRp reaches 62% (in BUNV).

The М-segment of KHURV is shorter than those of the orthobunyaviruses (3,161 nt vs. 4,451 nt for BUNV). The М-segment of KHURV has a single ORF (2,997 nt), which encodes a polyprotein precursor (998 aa) of the envelope glycoproteins Gn and Gc. Apparently, the M-segment of KHURV does not contain a nonstructural protein NSm, which is common in most of the orthobunyaviruses. 8, 9 The putative cleavage site between Gn and Gc of KHURV was found in position 319/320 aa (ASA/EN). This site corresponds to the cleavage site between NSm/Gc of the orthobunyaviruses and the conservative amino acid A/Е (VAA/EE in BUNV). The size of the Gn protein of KHURV is the same as that of the other orthobunyaviruses, 320 aa. The similarity of KHURV Gn is 23À29% aa, on average, to that of the other orthobunyaviruses (28.5% aa to BUNV). The size of the Gc protein of KHURV, 679 aa, is shorter than that of the other orthobunyaviruses (cf. 950 aa for the Gc protein of BUNV). The C-part (approx. 500 aa) of the Gc protein, which includes the conservative domain G1 (pfam03557), has about 30% aa similarity to the C-part in the other orthobunyaviruses, whereas the N-part (approximately 170 aa) has no similarity to that of any proteins in the Genbank database. The S-segment of KHURV is 950 nt in length and encodes a nucleocapsid protein (227 aa). The similarity of the N protein to that of the orthobunyaviruses is 22À26 aa%. Most orthobunyaviruses have an additional ORF that encodes Arthropod Vectors. There are no known arthropod vectors of KHURV; the virus has been isolated only from birds. More than 20,000 Aedes, Culex, and Anopheles mosquitoes were examined during the survival period for arboviruses in this region, and no KHURV isolations were obtained. The family Ceratopogonidae of biting midges is a potential vector of KHURV, but these insects have not been surveyed. Vertebrate Hosts. All isolations of KHURV were obtained from birds. Nine strains of the virus were isolated from coots (Fulica atra). (One hundred seventeen birds were examined and were found to have an infection rate of 8.5%.) One strain was isolated from the pygmy cormorant (Phalacrocorax pygmaeus). (Two hundred eighty-nine cormorants, mostly Ph. carbo, were examined and were found to have an infection rate of 0.3%.)

The Phlebovirus genus comprises about 70 viruses that are divided into two main groups based on their ecological, antigenic, and genomic properties: mosquito-borne viruses and tick-borne viruses. 1, 2 The genome of the phleboviruses consists of three segments of ssRNA with negative polarity: L (about 6,500 nt), M (about 3,300À4,200 nt), and S (about 1,800 nt) (Figure 8 .36). In general, the structure of the genome is the same for mosquito-borne and tick-borne phleboviruses, but the M-segment is shorter in tick-borne viruses and it does not encode the nonstructural protein NSm. 3 Phylogenetically, the phleboviruses can be divided into two branches in accordance with their ecological features. The tick-borne phleboviruses comprise viruses of the Uukuniemi group, the Bhanja group, and the two novel related viruses severe fever with thrombocytopenia syndrome virus (SFTSV) and Heartland virus (HRTV), which form separate clusters and are unassigned to any group (Figures 8.37À8.39). The UUKV serogroup currently comprises 15 viruses, but the status of some of them may be revised with the accumulation of more genomic and serological data.

History. Bhanja virus (BHAV) was originally isolated from Haemaphysalis intermedia ticks that were collected from a paralyzed goat in the town of Bhanjanagar in the Ganjam district in the state of Odisha, India, in 1954 and was assigned to the unclassified bunyaviruses. 1 In Europe, the first isolation of BHAV was obtained from adult Haem. punctata ticks collected in Italy (1967) and then in Croatia and Bulgaria. 2,3,4 Palma virus (PALV), a virus closely related to BHAV, was isolated from Haem. punctata ticks in Portugal. 5 Two viruses-Kismayo virus (KISV) and Forécariah virus (FORV)-antigenically related to BHAV were isolated in Africa. 6, 7 These viruses have been merged into the Bhanja group on the basis of their serological cross-reactions. 8, 9 In Transcaucasia, BHAV (strain LEIV-1818Az) was isolated from Ixodidae ticks Rhipicephalus bursa collected from cows in Ismailli District, Azerbaijan, in 1972 ( Figure 8 .40). Closely related to BHAV, RAZV (strain LEIV-2741Arm) was isolated from ixodid ticks Dermacentor marginatus collected from sheep near the village of Solak in the Razdan district of Armenia ( Figure 8 .40). 10, 11 Serological methods (detection of antibodies in animals and humans) have shown that BHAV circulates in many Mediterranean countries, the Middle East, Asia, and Africa. 12, 13 Taxonomy. Viruses of the BHAV group are not antigenically related to any of the other bunyaviruses, but they were assigned to the Phlebovirus genus on the basis of a genetic analysis of their full-length genome sequences. 14, 15, 16 Weak antigenic relationships were found between BHAV and SFTSV, a novel phlebovirus isolated in China. 16, 17, 18 SFTSV, in its turn, is antigenically related to viruses of the Uukuniemi group. 19 The genomes of certain viruses of the The M-segment of BHAV (3,307 nt) encodes a polyprotein precursor (1,069 aa) of the envelope glycoproteins Gn and Gc. Like the M-segments of other tick-borne phleboviruses, that of BHAV has no NSm proteins that are common to mosquitoes-borne phleboviruses. The predicted cleavage site between Gn and Gc proteins has been found by Signal IP software (http://www.cbs.dtu.dk/services) to be in position 559/560 of the polyprotein precursor (motif MHMALC/CDESRL). A dipeptide CD in the cleavage site is also typical for SFTSV and HRTV, which were associated with human disease in China and the United States, respectively. 17, 18, 22 Other phleboviruses, including UUKV and RVFV, contain a dipeptide CS in this position.

The S-segment (1,871 nt) of BHAV has two ORFs (N and NSs proteins) disposed in opposite orientations (an ambisense expression strategy) and separated by an intergenic spacer (139 nt) . The similarity of the nucleocapsid Vertebrate Hosts. The ungulates, including domestic cows, sheep, and goats, are apparently involved in the circulation of BHAV. 24 Usually, BHAV infection in adult animals is asymptomatic, but it is pathogenic to young ones (lamb, calf, suckling mouse), causing fever and meningoencephalitis. 13 ,25À27 Experimental infection of rhesus monkeys by BHAV induced encephalitis. 28 Several strains of BHAV were isolated from the four-toed hedgehog (Atelerix albiventris) and the striped ground squirrel (Xerus erythropus) in Africa. Antibodies have been detected in dogs, roe deer (Capreolus capreolus), and wild boars (Sus scrofa). 12 Human Pathology. BHAV infection in human is mainly asymptomatic, but several cases of fever and meningoencephalitis caused by BHAV have been described. 29À31

History. Gissar virus (GSRV) was isolated from Argas reflexus ticks collected in a dovecote in the town of of Gissar in Tajikistan (38 40 0 N, Taxonomy. The genome of GSRV (strain LEIV-5995Taj) has been sequenced. 4 Phylogenetic analysis shows that GSRV is a member of the Phlebovirus genus of the Uukuniemi group (Figures 8.37À8.39 ). GSRV is closely related to Grand Arbaud virus (GAV), which was isolated from a pool of Argas reflexus ticks collected in a dovecote near Gageron in Arles in the Rhô ne River delta in the Camargue region of France in 1966. 5 GAV is classified as virus belonging to the Uukuniemi group. 6 The identity of the nucleotide and amino acid sequences of GSRV and GAV is 76% nt for the S-segment (94% aa for the nucleocapsid protein), 73% nt for the M-segment (82% aa for the polyprotein precursor of Gn/Gc), and 76% nt for the L-segment (87.5% aa for RdRp).

Arthropod Vectors. Regardless of their geographical distribution, GSRV and GAV occupy a narrow ecological niche associated with ticks (Argas reflexus) and birds (most likely, pigeons (Columbidae)). In laboratory experiments, GSRV reproduced in A. reflexus ticks in 30 days with titers up to 2.0 log 10 (LD 50 )/20 mcL. 7 The distribution of Argas reflexus ticks is limited between 51 N on the north and 31 N on the south. The A. reflexus metamorphosis cycle is about three years. The ticks inhabit pigeons' habitats, which are also used by other birds, such as swallows and swifts. A. reflexus larvae were found in Europe on a rock swallow (Ptyonoprogne rupestris), in Egypt on a little owl (Athene noctua), in Israel on a rock dove (Columba livia) and a fan-tailed raven (Corvus rhipidurus), and in Crimea on the western jackdaw (Corvus monedula). The mass reproduction of mites in a dovecote has a negative impact on pigeons' bereeding behavior. Worse, at night the ticks can go down to the living space and bite people if the dovecote is built into a house. 8 Vertebrate Hosts. The main vertebrates involved in the circulation of GSRV are apparently birds, particularly the Columbidae. In laboratory experiments, GSRV was isolated from the blood of small doves (Streptopelia senegalensis) 5, 9, 22, and 30 days after infection. The virus titer in the blood was 1.5À2.5 log 10 (LD 50 )/20 mcL, on average. Serological examination of birds in Tajikistan found antibodies to GSRV 2% of doves (Columba livia). 7

History. Khasan virus (KHAV) was isolated from Haemaphysalis longicornis ticks collected from spotted deer (Cervus nippon) in 1971 in the forest in Khasan District in the south of Primorsky Krai, Russia (Figure 8.43 ). 1 Morphologic studies showed that KHAV belongs to the Bunyaviridae family. The virion of KHAV has structural elements (filaments up to 10 nm) that are typical for UUKV, but no antigenic relationships between KHAV and UUKV (as well as Zaliv Terpeniya virus, ZTV) have been found. 1, 2 In a complement-fixation test, KHAV did not react with serum used in the identification of certain bunyaviruses, so it was categorized in with the unclassified bunyaviruses. 3 Taxonomy. The genome of KHAV (strain LEIV-Prm776) was sequenced, and the virus was classified into the Phlebovirus genus of the Bunyaviridae family. 4 The genome of KHAV consists of three segments of ssRNA whose size and ORF structure correspond to the size and ORF structure of the other tick-borne phleboviruses. A full-length pairwise comparison of L-segments revealed a 53.1% nt identity between KHAV and UUKV and 45.3% between KHAV and RVFV. The predicted amino acid sequence of RdRp of KHAV has 48.6% and 35.3% aa identities with UUKV and RVFV, respectively. As in other tick-borne phleboviruses, the M-segment of KHAV does not contain any NSm protein. The similarity between the M-segments of KHAV and UUKV is 45.6% nt, and that between the polyprotein precursors of KHAV and UUKV is 35.9% aa. The S-segment of KHAV has 35% nt (25.5% aa for the N-protein) identity, on average, with that of the Uukuniemi group viruses and 35% nt (27.8% aa), on average, with the mosquitoborne phleboviruses.

On phylogenetic trees constructed on the basis of the alignment of full-length genome segments, KHAV forms a distinct branch external to the Uukuniemi group viruses (Figures 8.37À8.39 ). At least 14 viruses with unsettled taxonomy are included in the Uukuniemi group. 5 Some of them can be considered variants of the species UUKV, Manawa virus (MWAV), Precarious Point virus (PPV), and GAV. Two tick-borne phleboviruses, SFTSV and HRTV, are more closely related to the Bhanja group than the Uukuniemi group. 6, 7 Arthropod Vectors. Only a single isolation of KHAV was ever obtained, and the ecology of the virus has not been studied. Haemaphysalis longicornis ticks, from which KHAV was isolated, are distributed in the Far East of Russia, the northeastern part of China, the northern islands of Japan, Korea, Fiji, New Zealand, and Australia. 8 Haem. longicornis ticks also are the main vector of SFTSV (oterwise called Huaiyangshan virus, HYSV), which caused a large outbreak of febrile illness with a high mortality rate (30%) in 2009 in China. 9 Vertebrate Hosts. The principal vertebrate host of KHAV is unknown. KHAV was isolated from ticks collected on deer. 1 Haemaphysalis longicornis ticks are repeatedly found on cows, goats, horses, sheep, badgers, and dogs. 8 

History. The sandfly fever virus group includes Naples and Sicilian subtypes. 1 Epidemics of the comparatively mild acute febrile disease of short duration brought on by these viruses in countries bordering the Mediterranean have been known since the Napoleonic Wars. 2 The same disease was common among newly arrived Austrian soldiers on the Dalmatian coast each summer. 3 Experiments conducted by an Austrian military commission proved that the disease was caused by a filterable agent in the blood of patients and that the sandfly Phlebotomus papatasi can serve as a vector to transmit the disease. 4 During World War II, epidemics occurred among troops in the Mediterranean and two antigenically distinct strains were isolated from the blood of patients in 1943 in Sicily and Naples. These strains have been designated the sandfly fever Sicilian virus (SFSV) and sandfly fever Naples virus (SFNV), with prototype virus TOSV. 5,6 Dr. A. Sabin gave a clinical description of the disease and demonstrated that immunity developed to one type of virus does not protect from infection caused by the other type. Later, several viruses related to SFNV (Anhanga (ANHV), Bujaru (BUJV), Candiru (CDUV), Chagres (CHGV), Icoaraci (ICOV), Itaporanga (ITPV), and Punta Toro (PTV)) were isolated from humans and rodents in South America. 2, 3, 7 To date, viruses related to TOSV have been found in all regions of the world, including the Palearctic, Neotropical, Ethiopian, and Oriental zoogeographical regions. 2 The prototype strain of TOSV was isolated from Phlebotomus papatasi sandflies in 1971 in Monte Argentario in central Italy. 8 Two viruses antigenically related to TOSV-Karimabad virus (KARV) and Salehabad virus (SALV)-were isolated from Phlebotomus flies collected in 1959 near Karimabad village and Salehabad village, respectively, in Iran. 9, 10 Several related viruses were isolated in the Mediterranean: sandfly fever Cyprus virus (SFCV; 11 Adria virus (ADRV, Salehabad-like), isolated in Saloniki (alternatively, Thessaloniki), Greece; 12 and Massilia virus, isolated near Marseilles, France. 13 Epidemic outbreaks of sandfly fever whose agents could not be typified occurred in some central Asian countries and in Crimea during and after World War II and in Turkmenistan after the devastating earthquake of 1948. Antibodies to SFSV, SFNV, and KARV were found in the blood of humans in Tajikistan, Azerbaijan, and Moldova. 14 Antibodies were also found in wild animals in Turkmenistan: the great gerbil (Rhombomys opimus), the long-clawed ground squirrel (Spermophilopsis leptodactylus), and the hedgehog (Erinaceus auritus). Three strains of SFNV and two strains of SFSV were isolated in 1986À1987 from the blood of patients in Afghanistan. 14, 15 Taxonomy. The genome of TOSV consists of three segments of negative-polarity ssRNA: L-segment (6,404 nt in length), M-segment (4,214 nt) and S-segment (1,869 nt). Phylogenetic analysis revealed that viruses of the SFNV complex are divided into five genetic clades that differ in their geographical distribution: (i) from Africa (Saint Floris virus and Gordil virus (GORV)); (ii) from the western Mediterranean (Punique virus (PUNV), Granada virus (GRV), and Massilia virus); (iii) TOSV; (iv) viruses from Italy, Cyprus, Egypt, and India; (v) strains from Serbia and Tehran virus. 16 Distribution. SFNV and SFSV are distributed over those areas of the southern parts of Europe and Asia, and over those areas of Africa, which are within the range of the vector. 15 ,17À22 TOSV is distributed over Italy; Spain; Portugal; the south of France; Slovenia; Greece, including the Ionian Islands: Cyprus; Sicily; and Turkey. 13,17,23À32 Both the Naples and Sicilian strains were isolated from the blood of patients with febrile illness in the vicinity of Aurangabad, Maharashtra state, in northern India. Sandfly virus fever also circulates in western India, as well as in Pakistan. 33 The cocirculation of two TOSV genotypes was uncovered in the southeast of France. 13, 15, 33 A case of disease associated with TOSV befell a tourist returning from Elba to Switzerland in 2009, and another struck an American tourist returning from Sicily the same year. 27 TOSV from France is genetically different from that in Spain. 3, 13, 33, 34 Periodic outbreaks of sandfly fever occurred in the first half of the twentieth century in some central Asian republics, Transcaucasia, Moldova, and Ukraine.

Arthropod Vectors. The primary vector of SFNV and SFSV is Phlebotomus Papatasi; for TOSV, the primary vectors are Ph. perniciosus and Ph. perfiliewi. The viruses can be transmitted by the transovarial route and therefore may not require amplification in wild vertebrate hosts. 35 The infection rate of sandflies can reach 1:220. 36 The active period of Phlebotomus in the southern part of Europe lasts from May to September. Sandflies are peridomestic; the immature stages feed on organic matter in soil and do not require water, but are sensitive to desiccation and therefore are often found in association with humid rodent burrows.

Vertebrate Hosts. The main vertebrates involved in the circulation of SFNV are rodents, particularly the great gerbil (Rhombomys opimus) and the long-clawed ground squirrel (Spermophilopsis leptodactylus), as well as a hedgehog (Erinaceus auritus). The great gerbil is distributed over areas ranging from near the Caspian Sea to the arid plains and deserts of central Asia. The northern border of the animal's distribution is from the 213 8.1 FAMILY BUNYAVIRIDAE mouth of the Ural River on northward to the Aral Karakum and Betpak-Dala deserts, to the southern coast of Lake Balkhash, and thence to northern China and Inner Mongolia. The habitats of Rh. opimus are sandy and clayey deserts. TOSV was isolated from the brain of the bat Pipistrellus kuhlii. 8 Animal and Human Pathology. Sandfly virus fever does not cause disease in domestic or wild animals. The hosts of Phlebotomus sandflies are usually rodents, which may develop antibodies. Over 100 human experimental volunteers were infected at the time of World War II. 36, 37 The incubation period is between 2 and 6 days, and the onset of fever and headache in those patients was sudden. Nausea, anorexia, vomiting, photophobia, pain in the eyes, and backache were common and were followed by a period of convalescence with weakness, sometimes diarrhea, and usually leucopenia. Viremia was present 24 h before and 24 h after the onset of fever. 37 TOSV was established as the cause of one-third of previously undiagnosed human aseptic meningitis and encephalitis cases examined in central Italy. SFCV was associated with a large outbreak in the Ionian Islands of Greece. 28 ADRV is associated with serious illness with tonic muscle spasms, convulsions, difficulty urinating, and temporary loss of sight. Human disease frequently goes unrecognized by local health-care workers. Studies of antibodies in people indicate that the most infections occur in children. When large numbers of unimmunized adults are introduced into an endemic area, the incidence of disease can be high. Human exposure to sandflies can be reduced by repellents, air-conditioning, and screens on windows. Because sandflies have a flight range of not more than 200 m, human habitats can be constructed at a distance from potential domestic sandflies' breeding places, such as chicken houses and quarters for other farm animals. 19 

History. UUKV was originally isolated from Ixodes ricinus ticks collected in 1959 from cows in southeastern Finland. 1,2 Antigenically similar isolates (strains LEIV-540Az and LEIV-810Az) have been obtained from blackbirds (Turdus merula) and I. ricinus ticks collected in the foothills of the Talysh Mountains in the southeast of Azerbaijan in 1968 and 1969, respectively. 3À5 UUKV is distributed in the mid-and southern boreal zones of Fennoscandia and adjacent areas of the Russian Plain. Twelve strains of UUKV were isolated from I. ricinus ticks (the infection rate was 0.5%), and one strain from Aedes communis mosquitoes, in landscapes in the mideastern region of Fennoscandia. 6, 7 Three strains were isolated from I. persulcatus ticks collected in Belozersky District, Vologda Region, Russia, in 1979. 8, 9 UUKV was also isolated from the mosquitoes Ae. flavescens and Ae. punctor in the west of Ukraine, as well as at the border between Poland and Belarus. 10, 11 Twenty-eight strains of UUKV were isolated from I. ricinus ticks collected in Lithuania and Estonia in 1970À1971. 6,7,12À14 UUKV was isolated as well from birds and I. ricinus ticks in western Ukraine and Belarus. 11, 15, 16 In central Europe, UUKV was found in the Czech Republic, Slovakia, and Poland. 17À20 The prototypical strain LEIV-21C of ZTV was isolated from Ixodes uriae ticks collected in 1969 in a colony of common murres (Uria aalge) in Tyuleniy Island in Zaliv Terpeniya Bay in the Sea of Okhotsk). 21, 22 In accordance with the results of electron microscopy, ZTV was assigned to the Bunyaviridae family. Complement-fixation testing revealed that ZTV is most closely related to UUKV, but the two viruses are easily distinguishable in a neutralization test. 21, 22 More than 60 strains of ZTV were isolated from I. uriae ticks collected in colonies of seabirds on the shelf and islands of the Sea of Okhotsk, the Bering Sea, and the Barents Sea (Table 8 .23, Figure 8 .44). 9, 21, 23, 24 Two strains of ZTV were isolated from I. signatus ticks collected on Ariy Kamen Island in the Commander Islands, but their infection rate was less than 1:10,000 (,0.01%). 9 A similar virus was found in Norway. 25 One strain of ZTV (LEIV-279Az) was isolated from the mosquito Culex modestus collected in 1969 in a colony of herons (genus Ardea) in the district of Kyzylagach in the southeastern part of Azerbaijan (Figure 8.44 ). 3 Natural foci of ZTV and UUKV associated with bloodsucking mosquitoes (subfamily Culicinae) are found in continental areas in the European part of Russia, particularly Murmansk region. 7 Taxonomy. The viruses of the Phlebovirus genus can be divided into two main ecological groups: those transmitted by bloodsucking mosquitoes (subfamily Culicinae) and midges (subfamily Phlebotominae), together called mosquito borne, and those transmitted by ticks (tick borne). UUKV is a prototypical virus of the Uukuniemi antigenic group, which includes at least 15 related tick-borne phleboviruses (Figures 8.37À8.39 ). 26 The genome of UUKV consists of three segments of ssRNA: an L-segment 6,423 nt long, an M-segment 3,229 nt long, and an S-segment 1,720 nt long. The M-segment of UUKV, and indeed, that of all tick-borne phleboviruses, is shorter than the M-segment of mosquito-borne phleboviruses, owing to the absence of the nonstructural protein NSm, which is common in the mosquitoborne phleboviruses. Originally, ZTV was described as a virus closely related to UUKV. A full-length sequence comparison showed that the similarity of ZTV to UUKV is 77.3% nt identity of the L-segment (90.9% aa of RdRp) and 70.9% nt identity of the M-segment (81.5% aa).

Arthropod Vectors. Most isolations of UUKV and ZTV were obtained from Ixodes ricinus and I. uriae ticks, respectively. The infection rates of nymphs and larvae of I. uriae are 5 and 13 times lower, respectively, than that of the imago. These rates indicate a high frequency (8À10%) of transovarial transmission of ZTV. 7, 9 Probably, ZTV has a more pronounced ability to replicate in mosquitoes that are active in the subarctic climate zone (tundra landscapes) in July through the first half of August at temperatures sufficient for the accumulation of virus in the salivary glands. 7 Islands. In the Murmansk Region, which lies to the north of the European part of Russia, antibodies were found in 6% of common murres (U. aalge), 4% of black-legged kittiwakes (Rissa tridactyla), and 1% of voles (Microtus oeconomus). 7, 9 Apparently, ruminants could be infected by mosquitoes or by eating fallen birds. On the north coast of the Kola Peninsula, antibodies were found in 6% of thick-billed murres (U. lomvia), in 7% of blacklegged kittiwakes, and in 1% of voles. 7, 9 In central and eastern Europe, a number of vertebrate hosts are involved in the circulation of UUKV: forest rodents (Myodes glareolus, Apodemus flavicollis) and terrestrial passerine birds-the blackbird (Turdus merula), pale trush (T. pallidus), ring ouzel (T. torquatus), European robin (Erithacus rubecula), hedge sparrow (Prunella modularis), wheatear (Oenanthe oenanthe), European starling (Sturnus vulgaris), carrion crow (Corvus corone), magpie (Pica pica), brambling (Fringilla montifringilla), hawfinch (Coccothraustes coccothraustes), yellow bunting (Emberiza sulphurata), turtle dove (Streptopelia turtur), and ringnecked pheasant (Phasianus colchicus). 20,28À32 Viremia and long-term persistence of the virus were demonstrated in experimentally infected birds of many species. Specific antibodies were detected in cows and reptiles.

Human Pathology. An association was revealed between UUKV and different forms of disease, including neuropathy. 33, 34 A serological survey of 1,004 people in Lithuania concluded that antibodies existed in 1.8À20.9% of the population. Human antibodies to UUKV were detected in less than 5% of the human population in central Europe 33À35 and 13À14% in Belarus. 16 The people living in the tundra landscape had antibodies to ZTV in 3.3% of cases, while in the forest no such antibodies were detected (via a neutralization reaction). (Table 8 .24). In previous studies, RUKV was mistakenly included in the Sakhalin serogroup in the Nairovirus genus. 1 Taxonomy. The genome of KOMV (strain LEIV-13856) and RUKV (strain LEIV-6269) were completely sequenced, and the two viruses were classified into the Phlebovirus genus. 2,3 A full-length comparison showed that the genetic similarity between KOMV and RUKV is 93.0À95.5% nt. Among other tick-borne phleboviruses, KOMV and RUKV are most closely related to MWAV, which was isolated from Argas abdussalami ticks in 1964 in Pakistan. 4 The similarities of the genomes of KOMV and RUKV to that of MWAV are 67.1% nt for the L-segment (73.0% aa for RdRp), 59.6% nt of the M-segment (58% aa for the polyprotein precursor), and 66.8% nt for the S-segment (58.4% aa for the N-protein). In phylogenetic trees, KOMV and RUKV were placed into the Uukuniemi group (Figures 8.37À8 .39). 5 The ecology and area of distribution of KOMV and RUKV are the same as those of ZTV, which is closely related to UUKV. Several strains of ZTV isolated on the Commander Islands were sequenced, and no reassortants of ZTV with KOMV were found. 6, 7 Arthropod vectors. All isolations of KOMV and RUKV were obtained from Ixodes uriae ticks, the obligate parasite of Alcidae birds. The Commander Islands are located on the border of the temperate and subarctic climatic zones, and many different viruses belonging to the Bunyaviridae (ZTV, SAKV, PMRV), Flaviviridae (Tyuleniy virus, TYUV), and Reoviridae (OKHV) families have been isolated from I. uriae ticks collected from birds living in colonies there. 8À11 Note that the KOMV infection rate of the I. uriae ticks in the Commander Islands is 10 times less than the ZTV (1:900) and TYUV (family Flaviviridae, genus Flavivirus) infection rates of the same ticks.

Vertebrate Hosts. The main vertebrate host of KOMV and RUKV is apparently Alcidae birds, especially the common murre (Uria aalge), but their involvement in the circulation of KOMV and RUKV has not been studied sufficiently.

Human Pathology. UUKV group viruses, in general, do not play a role in human infectious pathology, although serological studies have detected antibodies to various viruses of this group in people.

The Flaviviridae family (from the Latin flavus, "yellow," as well as from yellow fever virus (YFV)) includes three genera: Flavivirus, Pestivirus, and Hepacivirus. 1 The Flaviviridae are small (40À60 nm) enveloped viruses. The genome is represented by ssRNA 

The Flavivirus genus includes more than 70 viruses classified into 15 antigenic groups. 1, 3 The Flavivirus virion is spherical (50 nm) and consists of a nucleocapsid (30 nm) and a lipid bilayer envelope covering it. The lipid envelope contains two transmembrane glycoproteins: M (matrix protein, 8 kD) and E (envelope protein, 50 kD). The genome of the flaviviruses is a single molecule of RNA about 11,000 nt in length and capped on the 5 0 terminus. The genomic RNA encodes a long ORF of a polyprotein precursor flanked by 5 0 and 3 0 untranslated regions. Mature viral proteins are produced during a complex process of proteolytic cleavage of the polyprotein precursor by cellular and viral proteases. Structural proteins (core, M, and E) occupy one-third of the RNA (the N part of the polyprotein) on the 5 0 part of the genome, followed by nonstructural proteins (NS1-NS5b) (Figure 8 .46). 2, 4 Most of the flaviviruses are arboviruses; that is, they can be transmitted to vertebrate hosts by bloodsucking arthropod vectors (Figure 8.47 ). Approximately 50% of known flaviviruses are transmitted by mosquitoes, about 30% by ticks. The arthropod vectors of some flaviviruses are unknown. There is also a group of flaviviruses that infect only insects and not vertebrates. Some flaviviruses (e.g., West Nile virus, WNV) have ecological plasticity and can be transmitted either by mosquitoes or by ticks. Flaviviruses are distributed over all continents, with mosquito-borne viruses found mainly in regions with an equatorial and tropical climate And tick-borne viruses found mostly in regions with a temperate climate zone. Many flaviviruses are associated with birds, which can transfer them during the birds' seasonal migration. Flaviviruses belongs to natural foci zoonoses. Certain flaviviruses, such as YFV, dengue virus (DENV), and West Nile virus (WNV), pose a serious threat to humans. 5À7

History. The first hint that Omsk hemorrhagic fever (OHF) was etiologically linked Figure 8 .48) an area with a wide network of lakes. About 200 cases with two lethal outcomes ("atypical tularemia" and "atypical leptospirosis") were investigated (without The expedition produced prodigious results: The prototype strain OHFV/Kubrin was isolated from the blood of one patient; the mechanism of transmission of the virus by the Ixodidae tick Dermacentor reticulatus was established; the epidemiological and clinical features of OHF, as well as its pathogenesis and pathomorphology, were described; and inactivated vaccine from mouse brain was developed and prepared for epidemiological trials. 5 Later, the role of another species of Ixodidae ticks (D. marginatus) as an OHFV vector was revealed. 8, 9 Taxonomy. OHFV belongs to the phylogenetic branch of the mammalian tick-borne virus group (Figure 8 .47). The OHFV genome has a length of 10,787 nt, and its organization is common to the flaviviruses. Two genotypes of OHFV are known today: Prototypical strains for the first one are OHFV/Kubrin and OHFV/Bogolubovska, which have an extremely small genetic distance between them; the prototypical strain for the second genotype is OHFV/uve. 10À12 Only six nucleotide substitutions, which encode four amino acids, have been found in the entire genome. Three of four amino acid changes were located in the envelope glycoprotein E. 11 Phylogenetic analysis based on a comparison of partial sequences of the E gene available in GenBank showed that OHFV isolates can be divided to three genetic lineages (Figure 8 .49).

The genetic diversity among strains of different lineage is up to 11.8%.

Arthropod Vectors. The natural foci of OHFV are found in the forestÀsteppe landscape zone of western Siberia, an area with numerous bogs and a wide network of lakes within the Omsk, Novosibirsk, Kurgan, and Tyumen regions (Figure 8 .48). The natural foci border the area of distribution of TBEV, and the two virus's natural foci are intermingled. 13À15 The principal Ixodidae tick vectors for OHFV are Dermacentor pictus (in the northern forestÀsteppe subzone) and D. marginatus (in the southern forestÀsteppe subzone). 3, 8, 9 The infection rate of D. pictus in epidemic years reaches 8%, in interepidemic years 0.1À0.9%. The main host for preimago phases of D. pictus is the narrow-headed vole (Microtus gregalis). This species of rodent is host to 70À90% of D. pictus nymphs and larvaein the northern forestÀsteppe subzone. In 1959À1962, when the number of Microtus gregalis voles fell significantly, there was a concomitant decrease in the number of D. pictus ticks in the center of an epidemic zone that was accompanied by a sharp decrease in the infection rate of ticks and an attenuation of the meadow natural foci of OHFV. In some of those years, however, a high number of Ixodes apronophorus, all phases of which feed on the water vole (Arvicola terrestris), become involved in the virus's circulation on a par with D. pictus ticks. Ar. terrestris makes fodder migrations in JuneÀAugust from damp locales (where their infection takes place) to coastal meadows (where peak activity of the larvae and nymphs of D. pictus is observed during those months). Small animals living in those meadows become infected as they feed on the D. pictus larvae and nymphs. In damp locales, I. apronophorus could infect muskrats. Also, D. marginatus, whose optimum zone lies in a steppe landscape belt, plays some (though largely insignificant) role in the lake areas of the southern forestÀsteppe subzone. 16 During epizootic and epidemic activity of OHF natural foci, Gamasidae ticks, as well as aquatic organisms belonging to the Hydracarinae, take part in OHFV circulation. Their involvement is confirmed by the identity of isolated strains with those isolated from muskrats and sick humans. Experiments with experimentally and spontaneously OHFVinfected Gamasidae ticks testify to the ability of longitudinal (more than six months) virus preservation. 17 Vertebrate Hosts. The principal vertebrate host of OHFV, which is able to directly infect humans, is the muskrat (Ondatra zibethicus). This species was introduced into western Siberia from Canada in 1928. Their population density reached a modern-day high in the 1940s. Close interactions among O. zibethicus and local populations of Arvicola terrestris emerged. Ar. terrestris has periods of rapid population growth followed by epizootics of tularemia, leptospirosis, and OHFV. Muskrats suffered these epizootics together with other local species of rodents: Microtus oeconomus, M. gregalis, Myodes rutilus, Apodemus agrarius, and Ar. terrestris. 13 The OFV infection rate among muskrats is about 15% in both the autumnÀwinter and the springÀsummer periods. 16 Latent infection was established in all rodents except the muskrat. 18 OHFV was detected in birds and in mosquitoes, but the role of these two animals in virus circulation is not clear. 18À21 Epidemiology. OHFV is transmitted both by Ixodidae tick bites and as the result of direct contact with infected muskrats, their flesh, and fresh fells. 1, 5 OHF morbidity during 1945À1949 reached 1.5À5.0%. Then there was a gradual decrease down to single cases. Most OHF cases (96.8%) were detected in the lake forestÀsteppe, in the south of the forestÀsteppe landscape zone, which occupies 14.5% of the territory where 15.3% of country people in the Omsk region live. The northern forestÀsteppe landscape zone is the youngest landscape of western Siberia, having evolved in place of the former southern taiga landscape zone. 22, 23 In the south of western Siberia, the following territorial zones can be marked out: (i) the 223 8.2 FAMILY FLAVIVIRIDAE preferred territory of Tick-borne encephalitis virus (TBEV) (the southern taiga); (ii) intermediate territory (the boundary of the southern taiga with the northern forestÀsteppe); (iii) the preferred territory of OHFV (the northern and southern forestÀ steppe); and (iv) the territory of sporadic cases of OHF (part of the southern forestÀsteppe and steppe). 13, 23 In the first zone, more than 90% of all cases of TBE in western Siberia are registered and only single OHF cases are found; in the second zone, 1% each of cases of TBE and OHF; in the third zone, 4% of TBE and 96% of OHF; and in the fourth zone, 4% of TBE and single cases of OHF. 13 The seasonal incidence of OHF distinctly correlates with the activity of the principal Ixodidae tick vectors. Cases (a few) of OHF acquired by direct contact with muskrats occur mainly during the season in which the animals are hunted, in OctoberÀJanuary. In the springÀ summer season, OHF cases occur chiefly in rural areas. The age of patients ranges from 5 to 70 years, but cases occur mainly among middle-aged persons (40À50 years old). In the autumnÀwinter period, OHF occurs mainly among muskrats trappers (60%), adult members of their families (28%), and children (12%). It appears that all patients infected directly from muskrats develop symptomatic illness. Seroprevalence ranges from 0 to 32% in populations of endemic regions. 3, 7, 23 In the last decade of the twentieth century, an increase in OHF natural foci activity took place in the Tyumen (1987), Omsk (1988, 1999À2007), Novosibirsk (1989À2002; regular epidemic activity took place on the territory of only four administrative districts), and Kurgan (1992) regions. In the absolute majority of laboratoryconfirmed cases, the nontransmissive pathway (direct contact with muskrats) of the infection dominated. 17 Pathogenesis is determined first of all by the destruction of capillaries, the vegetative nervous system, and the adrenal glands. 16, 24 Clinical Features. The incubation period of OHFV is 2À4 days long. The disease begins abruptly, with fever, head and muscular pain, hyperemia, and injection in the sclera. The body temperature increases up to 39À40 C and stays that way for 3À4 days, then decreases a little and critically falls on the 7th to 10th day after symptoms appear. From the first days of the illness, there are diapedetic bleedings, especially in the nose. Recovery is usually complete, without any residual phenomena; lethal outcomes are possible, but are rare. 16,24À26 Control and Prophylaxis. OHFV survives up to 20 days in lake water. Water can be contaminated by urine and feces of the infected muskrats or some other rodents. The water pathway in human infection has been discussed in the literature. 13, 14 Prevention of the infection depends on the use of protective respirators and rubber gloves in processing muskrat pelts and on personal protective measures against tick bites. TBE vaccine offers a high degree of protection against OHF. 10, 23 Cases of laboratory-acquired OHF have been reported in unvaccinated persons, and TBE vaccine is recommended for laboratory personnel working with either virus. 23 Interferon and its inductors have shown a high efficiency in preventing OHF in experiments using animal models. 27 The genome of POWV is a about 10,835 nt in length. The virus comprises two genetic lineages, formed by POWV (lineage I) and the closely related deer tick virus (DTV, lineage II) (Figure 8 .51). 8 Phylogenetic analysis based on partial sequences of the E gene showed that the population of POWV in Russia has a low genetic diversity. 9 The strains of POWV isolated in Russia have a high genetic similarity to the strains of lineage I isolated in North America. A full-length genome comparison revealed that Far Eastern isolates (LEIV-3070Prm, Spassk-9, and Nadezdinsk-1991) have a 99.5% identity with strain POWV/LB from Canada (Figure 8.51) .

Arthropod Vectors. POWV was isolated from Ixodidae ticks collected in the Russian Far East and in the U.S. states of California, Colorado, Connecticut, Massachusetts, South Dakota, and West Virginia. Serological investigations of wild mammals indicate that POWV also circulates in the Canadian provinces of Alberta, British Columbia, and Nova Scotia. 3,10À12 In North American natural foci, POWV was isolated from Ixodes cookei, I. spinipalpus, I. marxi, and Dermacentor andersoni ticks. 3, 10, 11 In the Far East, known vectors of POWV are Haemaphysalis longicornis, Haem. concinna, Haem. japonica, D. silvarum, and I. persulcatus ticks. 5, 9, 13, 14 Transphase and transovarial transmission of POWV in Ixodidae ticks has been established.

Vertebrate Hosts. In North America, POWV was isolated from wild mammals: the woodchuck (Mormota monax, the main reservoir), American red squirrel (Tamiasciurus hudsonicus), deer mouse (Peromiscus maniculatus), red fox (Vulpes fulva), eastern gray squirrel (Sciurus carolinensis), North American porcupine (Erethizon dorsatum), striped skunk (Mephitis mephitis), raccoon (Procyon lotor), long-tailed weasel (Mustela frenata), and gray fox (Urocyon cinereoargenteus). 2, 4, 15 Infection of wild vertebrates most often is inapparent. 2, 10 In the south of the Russian Far East (in Primorsky Krai), POWV was isolated from aquatic birds: the common teal (Anas crecca) and the mallard (Anas platyrhynchos). 9, 13, 14, 16 Epidemiology. Human infections of POWV were reported in Canada (Ontario and Quebec), the United States (New York and Pennsylvania), 2 and Russia (Primorsky Krai). 14, 17, 18 Nevertheless, human infection rarely develops.

Clinical Features. The clinical picture of developing meningitis and encephalomeningitis includes high temperature, dryness in the gullet, drowsiness, headache, disorientation, convulsions, vomiting, difficulty breathing, coma, and paralysis, with 11% lethality in the severe phase of the disease. Autopsy has revealed widespread perivascular and focal parenchymatous infiltration. In 50% of recoveries, consequent damage to the CNS develops, which could lead to death in 1À3 years. 2, 18 Control and Prophylaxis. The vaccine against TBEV is not effective against POWV. 2 History. In 1931À1934, the Russian military medical doctorÀneuropathologist A.G. Panov, together with his colleagues A.N. Shapoval and D.A. Krasnov, described a neuroinfection with a high level of mortality in the Far East. This neuroinfection later was called "springÀ summer encephalitis." 1,2 During field expeditions in 1937À1940, the historical strain TBEV/ Sofjin was isolated from the brain of a patient with encephalitis who died in Khabarovsk Krai (Figure 8.52) . In that period, the main vector of TBEV-Ixodes persulcatus tickswas established, epidemiological peculiarities of TBE were studied, and the first anti-TBEV vaccine was developed on the basis of intracerebrally infected mouse brain and was successfully used in medical practice. 2 Complex expeditions were undertaken by a number of prominent virologists (L.A. Zilber (Figure 2.9 Strain TBEV/LEIV-1380Kaz (the former AAV) was isolated from Ixodes persulcatus in the low-mountain part of southeastern Kazakhstan (Alma-Ata Region) in 1977. 11 Preliminary investigation revealed a one-sided antigenic relation between AAV and POWV. 12 AAV was associated with human cases of meningitis. Specific antibodies to AAV were found among ground squirrels (Citellus fulvus), agricultural animals, and humans. Later, the AAV genome was sequenced (GenBank ID: KJ 744033). 13 A full-length genome comparison showed that AAV has the highest similarity (94.6% nt and 98.3% aa identities) to the TBEV/ Chita-653, TBEV/Irkutsk-12, TBEV/Aino, and TBEV/Vasilchenko strains belonging to the Siberian genotype (Figure 8.53) .

Recent genetic studies of TBEV revealed two additional genotypes of this virus on the territory of eastern Siberia (Irkutsk Region): for the first one, only a single strain is known today; for the latter, there are five strains in Mongolia. 14 Thus, TBEV has a high level of genetic diversity in Northern Eurasia. TBEV-Sib genotype dominates in Europe, western Siberia, and eastern Siberia, TBEV-FE in the Far East. 15, 16 The TBEV-FE genotype, which was widely distributed in Siberia and northeastern Europe, is now being displaced by TBEV-Sib. TBEV-FE strains are often pathogenic to laboratory mice, whereas TBEV-Sib frequently provokes severe and lethal disease. 15 Local populations of all genotypes of TBEV could be stable for a long time. 16 Distribution. TBEV is distributed within the areas of distribution of its main vectors: Ixodes persulcatus and I. ricinus ticks (Figure 8 .54-see details in the detailed work of E.I. Korenberg 17 Norway; 29À31 in the rest of Europe, the Czech Republic, 8, 32 Slovakia, 6, 33, 34 Bulgaria, 35 Hungary, 36, 37 Poland, 38, 39 Croatia, 40 Latvia, 41 Lithuania, 42 Estonia, 43, 44 Denmark, 31 Germany, 45À48 Austria, 49 Slovenia, 50 France, 51 Italy, 52,53 and Spain 54 (Table 8 .25); And in Asia, the Russian Far East and Siberia, 1,16,55 Japan (Hokkaido), 55 North and South Korea, 56, 57 China, 58 Mongolia, 59 Kazakhstan, 13 and Kyrgyzstan. 60 Arthropod Vectors. Natural TBEV infection has been observed in 16 species of Ixodidae ticks. The principal arthropod vectors for TBEV in Russia are the Ixodidae ticks Ixodes persulcatus (in the Far East, Siberia, and the north of the European part of the country) and I. ricinus (in the south of the European part) (Figure 8.54 ). 69 The northern boundary of I. persulcatus and I. ricinus lies within the limits of an effective temperature sum isoline of about 1,000À1,300 C (the middle taiga landscape belt). The most suitable climatic conditions for these ticks are within the south taiga. Imago tick activity begins in the third d decade of April and reaches a maximum in the second and third decades of May or in the first and second decades of June, with activity beginning to decrease in the third decade of June. This time frame correlates with morbidity dynamics having an 8-to 10-day lag (Figure 8 .55). 70 The ecological links of TBEV during its circulation in natural foci are extremely diverse as the result of wide distribution of this virus (Figures 8.52 and 8.54 ). Ixodidae ticks, mainly I. persulcatus, are the natural reservoir of TBEV and the core of natural foci. 12, 62, 71, 72 From the very beginning of the tick's larval stage, a suctional, tarlike liquid appears around the hypostome and becomes rosin. 62, 73 The quantity of virus in this rosin plug is comparable to that in the tick's body (10 3 À10 4 PFU/mcL). 74 The place of suction on the body of the host is significant for the development of infection; for example, suction in the axillary hollow results in the highest lethality (16.1%, 1.5 times more in comparison to suction in the neck and in the head. 73 Ticks become infected as they suck blood from a vertebrate host with a level of viremia that is equal to or higher than the threshold required for infection. Ticks can also become infected from an uninfected vertebrate host as they suck blood together with infected ticks. 73, 75 Transovarial and transphase transmission of TBEV has been described in the literature; nevertheless, the effectiveness of vertical transmission of TBEV is low. (About 1% of progeny turn out to be infected). 52, 76 The sexual pathway of TBEV transmission from male to female is quite effective (about 50%). 77À79 The aggressiveness and activity of TBEV-infected Ixodidae ticks increases with the TBEV titer in their bodies. 62, 75 Infected ticks have been found on the clothing of FIGURE 8.55 Trends in the incidence of TBE in Russia, by month (as a percentage of the amount of disease for the year, according to long-term data).

humans at a fequency 5À20 times higher than uninfected ticks have been found. 48, 62, 75 TBEV has been isolated from the mosquitoes Anopheles hyrcanus in Kyrgyzstan 80 and Aedes sp. in western Siberia. 81 The strain TBEV/Malyshevo was isolated from Aedes vexans nipponii mosquitoes collected in 1978 on the coast of Petropavlovskoe Lake in Khabarovsk Krai in the Russian Far East (48 40ʹN, 135 41ʹE ). 82À84 A preliminary investigation 82 concluded that this strain belonged to Negishi (NEGV) virus, 85 and later the possibility was discussed that the strain belonged to a separate, Malyshevo virus. Then, phylogenetic analysis using a next-generation sequencing approach revealed that Malyshevo is a strain of TBEV and is closely related to TBEV strains isolated in the Far East: TBEV/1230, TBEV/ Spassk-72, TBEV/Primorye-89. 13 TBEV has been isolated many times fromticks and fleas of the superfamily Gamasoidea living in nests of rodents and birds (Table 8 .27), even during the winter period. 2,47,86À89 Vertebrate Hosts. Hosts for the preimago stage of Ixodidae ticks-Asian chipmunks (Tamias sibiricus), shrews (members of the Soricidae family), bank voles (Myodes glareolus), field voles (Microtus agrestis), mountain hares (Lepus timidus), and 74 species of birds (Table 8 .28)-have great significance in TBEV circulation. 10, 12, 62, 64, 71, 72, 90, 91 Persistent TBEV infection in bank voles and field voles has been found during the winter period. 26 Infection among vertebrates occurs mainly by tick bites. In rare instances, alimentary transmission of TBEV through milk containing viruses is possible. 34, 92 Epidemiology. There are two basic modes of human infection by TBEV: (i) as the result of being bitten by infected Ixodidae ticks (the main mode); and (ii) as the result of consuming infected raw goat, sheep, and cow meat, milk, or dairy products (mainly in natural foci linked to Ixodes ricinus). 23, 32, 93 The latter pathway of TBEV distribution often involves whole families. As much as 70% of cases in Belarus have been alimentary. 70 TBEV can persist in milk at 60 C for more than 10 min, and some of the viruses can remain viable even after pasteurization at 62 C for 20 min. Nor is TBEV inactivated after 24 h at 4 C and pH 2.8. Many laboratory infection cases (usually by aerosol) have been described.

Several hundred cases are recorded in Europe (Table 8 .25) and in Russia (Table 8.26 ) each year, with considerable interannual variation. 17,70,94À96 The highest level of TBE morbidity is registered in the Baltic states (Latvia, 6.2À10.8 per 100,000 population); Lithuania, 6.5À13.5; and Estonia, 10.4À13.5) and in Slovenia (10.2À18.6) and the Czech Republic (5.0À10.0). In neighboring Austria, where the vaccination rate is higher, the index is lower (0.6À1.2). 97 Seasonal TBE morbidity in Russia is connected with seasonal activity of the Ixodidae tick vectors (Figure 8.55) .

The risk of infection depends upon the frequency of tick bites, which is different for populations living in the different landscape belts. Results of an investigation of almost 200,000 people demonstrate that the highest risk is for the population living in the southern taiga belt, where about 20% of adults were found to have tick bites during one epidemic season (Table 8. 

In rural localities of the southern taiga belt, about half of schoolchildren and about 80% of adults have antibodies to TBEV. For comparison, only 14À20% of adult citizens of Kemerovo, a city of about half a million in western Siberia, and 2À3% of citizens of Moscow have antibodies specific to TBEV (Table 8.29) . 98 A mathematical model for evaluating the infection rate and the probability of developing the disease as a function of the density of the tick population, its infection rate and biting activity, and the level of the immune human layer was developed by D.K. Lvov and coauthors. 98À102 The same approach, which is also suitable for other arboviral infections, was used for landscape-epidemiological zoning of TBEV natural foci in Altai Krai in the southern part of western Siberia: More than 10,000 residents living in the different landscape belts on a territory about 250,000 km 2 were tested by serological methods (Figure 8.56) . The tests produced a good fit between calculated and registered morbidity data (Table 8.30) .

Pathogenesis. TBE can be realized in several pathogenetic variants. An inapparent clinical form is characterized by short-term localization of TBEV in lymph nodes and immune cells, as well as by extranervous reproduction without viremia. Infection is terminated by the development of stable immunity. About 95% of cases of infection are inapparent. 102 Clinical fever is expressed as a common infectious process, but both the central and the peripheral nervous system are involved in the pathology. 103 Neuroinfection is characterized by lesion of the envelope and substance of the spinal cord and CNS.

Clinical Features. The incubation period ranges from 1 to 30 days, but usually is 7À12 days. The onset of illness in typical cases is abrupt and with a headache. The temperature Clinical symptoms of TBE, as well as the severity of the disease, are at least partially determined by biological properties of the virus. 104 There are two main clinical forms of TBE: the Far Eastern variety, associated with Far Eastern and Siberian strains of the virus, and the European variety (also known as Western biphasic meningoencephalitis or biphasic milk fever), associated chiefly with European strains. Human disease of the first type is usually clinically more severe in the acute phase, but is associated with a lower rate of chronic CNS sequelae.

The first phase starts with sudden fever, flulike symptoms (pronounced headache, weakness, nausea, myalgia, arthralgia), and conjunctivitis. The second phase appears after 4À7 days of apparent recovery, but then the CNS is affected (meningoencephalitis appears), accompanied with fever, retrobulbar pain, photophobia, stiff neck, sleeping disorders, excessive sweating, drowsiness, tremors, nystagmus, meningeal signs, ataxia, pareses of the extremities, dizziness, confusion, psychic instability, excitability, anxiety, disorientation, and/or memory loss. TBEV produces diffuse degenerative changes in neurons, perivascular lymphocytic infiltration, and damage to Purkinje cells in the CNS. Mortality ranges from 1% (TBEV-Eur), to 8% (TBEV-Sib), to 20À40% (TBEV-FE). Convalescence is prolonged, and neurological and psychotic sequelae often include paresis and atrophic paralysis of the neck and shoulders. 27, 45, 104 A chronic form of the disease occasionally combines with a progressive course (called Kozhevnikov's epilepsy), in which progressive neuritis of the shoulder plexus, multiple sclerosis, and progressive muscle atrophy often develop. 105, 106 The chronic form is registered in 1À2% of all TBE cases and is said to be the result of virusÀimmunity interactions. 19 Many authors have noted a decreasing number of severe TBE cases. 103 Diagnostics. Laboratory diagnosis of TBE involves both serological (ELISA, hemagglutination inhibition test (HIT), neutralization testing) and virological methods (virus isolation using a biological model of intracerebrally inoculated newborn mice, 5À6 g mice, cell culture), as well as highly sensitive RT-PCR and real-time RT-PCR.

Control and Prophylaxis. Specific and nonspecific prophylaxis tools are highly efficient if they are utilized correctly. Personal safety includes protection against ticks. Vaccination against TBEV has a long history of success. Mass vaccination of populations in the endemic territory is necessary. A full course of vaccination provides 98% safety. 102 All vaccines produced in Russia are effective in the entire area of distribution of TBEV, independently of the strain used to prepare the vaccine. Vaccination has reduced TBE morbidity down to single cases in Austria, the Czech Republic, and Slovakia. 107 Single cases of TBEV among vaccinated persons need to be investigated because possible causes are personal peculiarities of the immune system and errors in the control of vaccine production. 108 The presence of brain tissue in vaccines produced on the basis of intracerebrally inoculated newborn mice was a source of danger for a long time: Demyelinating encephalitis could develop. This danger was eliminated after vaccines were developed which used TBEV strains that reproduced in cell cultures. In the 1960s, cell culture vaccines against TBEV were developed by E.N. Levkovich History. Japanese encephalitis virus (JEV) was originally isolated by H. Hayashi in 1933 from a patient who died with encephalitis and then, again, in 1935 from a patient who died with a fever in Tokyo. 1, 2 Before that, however, Japanese encephalitis (JE) epidemics was documented in Japan in 1903 and onward as "Ioshiwara cold." In the south of the Russian Far East, strains of JEV were known since the end of the 1930s (Figure 8.57 ).

JE played a role in the historical events of World War II. American military personnel massed on Okinawa and preparing to invade Japan were demoralized by an outbreak of encephalitis among the indigenous people. A fictionalized account of the risk from JE for American soldiers during World War II underscores the military risk. 3 Taxonomy. Phylogenetic studies indicated that JEV isolates be divided into five genotypes, the distributions of which overlapped (Figure 8.58 ). Genotypes I, II, and III are most prevalent and are spread throughout Asia (Japan, China, India, Korea, Malaysia, and Vietnam), the Far East of Russia, and northern Australia. Genotypes IV and V are rarer and were isolated in Indonesia and India, respectively. Genotypes I and III are found mostly in temperate zones, whereas genotypes II and IV predominate in tropical zones. 4À6 Genetic diversity between strains of the different genotypes ranges from 9.1% to 16.6%.

Arthropod Vectors. JEV circulation in the equatorial and subequatorial climatic zones is year-round and is seasonal in the tropical, subtropical, and temperate belts, with a peak at the end of summer and the beginning of fall. JEV is brought from the equatorial and tropical climatic belts to the subtropical and temperate belt during the spring migration of birds.

About 30 species of mosquitoes are able to transmit JEV; nevertheless, only some of them are effective vectors. The main vector in Japan, the Philippines, the Korean Peninsula, China, the Indochinese Peninsula (except Malaysia), Indonesia, Sri Lanka, India, and Nepal is Epidemics usually develop after plentiful precipitation and a long rise in environmental temperatures until they are no less than 25 C (but within the range 25À32 C). 7 For a long time, the main vector for JEV in the south of Primorsky Krai in Russia was Culex tritaeniorhynchus. In the 1940s, as a result of both improvements in agriculture and meteorological changes, this species of mosquitoes consisted about 80% of all field collections. In subsequent years, however, their numbers abruptly declined, and by the 1960s the species represented only 0.15À0.75% of all mosquitoes collected. Cx. pipiens is an accessory vector, and Aedes togoi transmits JEV in seashore areas. JEV was also isolated in 1989 from Ae. vexans. 8, 9 Vertebrate Hosts. Aquatic and semiaquatic birds (especially herons) have the main significance in the natural cycle of JEV circulation. Regular transfer of JEV in migratory birds from endemic territories with year-round circulation of the virus to regions of the southern part of the temperate climatic belt (in particular, the southern part of Primorsky Krai, to the south from Lake Khanka 11 ) is likely. 10 JEV transfer over hundreds of kilometers by infected mosquitoes is possible as well, especially in areas with a monsoonal climate (e.g., in Australia through the Torres Strait 12À14 ). Birds transfer JEV from natural to synantropic biocenoses, where, thanks to Culex tritaeniorhynchus mosquitoes willingly attacking wild birds, pigs, persons, synantropic birds, and domestic animals (chiefly pigs), these all join into JEV circulation. 7 Infection in pigs could be inapparent, or it could be clinically expressed with encephalitis and a lethal outcome. The level of viremia in infected pigs is enough to infect mosquitoes. Such epizootics among pigs are, in effect, amplifiers for JEV, serving as prerequisites for the development of epidemics, first of all among people living in the countryside, but then among city dwellers as well.

Antibodies to JEV specifically were revealed among wild boars (83%), raccoons (59%), 14 and dogs (17%). 7 In the south of China, JEV was isolated from both Leschenault's Rousette (Rousettus leschnaulti), a species of fruit bat, and the little tube-nosed bat (Murina aurata), 15 and anti-JEV antibodies were identified in the blood of those animals. 16 JEV preservation in bats could be one of the mechanisms of the year-round circulation of the virus in its natural foci, with activation in the spring and subsequent replication and spreading in the summer and autumn.

In natural foci, birds are the principal vertebrate hosts contributing to transmission of the virus; in synantropic foci, pigs are the most important vertebrate hosts. 10,11 JEV has been isolated from the grey-headed bunting (Emberiza fucata), great cormorant (Phalacrocorax carbo), Japanese thrush (Turdus cardis), azure-winged magpie (Cyanopica cyana), Japanese wagtail (Motacilla grandis), barn swallow (Hirundo rustica), and night heron (Nicticorax nicticorax). Natural foci are situated in meadows. Of late, Culex tritaeniorhynchus has become more abundant in connection with intensive rice cultivation, portending the possibility of increased JEV circulation and epidemics. 17, 18 Epidemiology. All the territory of Japan, except for northern part of Hokkaido, 7 is endemic, but most diseases are registered near islands in a closed sea, as well as in Tokyo and adjacent prefectures. 3 Before 1966, outbreaks of JE emerged in Japan practically every year, with 1,200À2,700 patients seen.

Later, morbidity began to decrease to tens of cases per year. In the 1970a and 1980s, morbidity fell to the level of single cases per year. The main cause of the decrease was a significant drop in the population of the main JEV vector-Culex tritaeniorhynchus mosquitoes-as the result of a reduction in the acreage of rice fields as well as water pollution in places of mosquito habitation. In addition, the program of mass vaccination carried out annually among children of school age and a change in the structure of pork farms lessening the availability of pigs played a significant role in the falloff in the mosquito population.

JE is a serious problem in 20 countries of southeast Asia and Oceania. 19 During the last few years, more than 50,000 cases per year were registered, with about 20% lethality. 19 Morbidity increases annually in Bangladesh, Indonesia, Laos, Myanmar, North Korea, and Pakistan. 19, 20 In addition, , the occurrence of an epidemic in southeastern Asian countries is becoming more and more likely because those countries are now seeking to increase their production of rice. The greatest risk of JE is said to be in China, Nepal, Sri Lanka, Thailand, 21 Laos, and Vietnam. JE is of the highest importance among all kinds of endemic encephalitis, potentially threatening nearly 50% of the population of our planet. 3 The disease especially affects military contingents, as it did the American army during the concentration of armies in Okinawa 3 and the Soviet army during the Battle of Lake Khasan (also called the Changkufeng Incident) in the south of Primorsky Krai.

Precursors of JEV circulated in Indonesia and then evolved into six genotypes. 22 Genotype III is widespread in a moderate climatic belt and often provokes epidemic outbreaks in eastern and southeastern Asia. Genotype I originated in Indonesia, circulated in Thailand and Cambodia in the 1970s and in South Korea and Japan in the 1990s, and has now completely replaced genotype III. 23 Genotype I got into Japan in two ways: from southeastern Asia and from mainland China. 24, 25 Two island territoriesthe Philippines and Taiwan, in both of which genotype III circulates-were free of genotype I-and the Philippines remains free-but the genotype appeared in Taiwan in 2008. 26 The evolution of JEV led to the emergence of two new subclusters in 2009À2010; the two together have replaced genotype III. Until recently, the Qinghai-Tibet Plateau, in China, was free of JEV, but in August 2009 the virus was isolated from Culex tritaeniorhynchus mosquitoes there. 27 During an epidemic in SeptemberÀNovember 2009, genotype I circulated in Japan. 28 In Nepal, on the northern border of India, JE has been known since 1978, after which outbreaks were observed annually. 9 JEV circulates in the north of Australia as well. 12, 21 JE claimed morbidity in the south of the Russian Far East (in Primorsky Krai) in 1938 during an expedition headed by P.G. Sergiev and I.I. Rogosin. Epidemics of JEV broke out in the region in 1938, 1939, and 1943. More than 800 cases were recognized between 1938 and 1943, with 68% reported in the extreme south of Primorsky Krai. The northern extent of this area is limited by the southern part of the Ussuri Lowland (about 42À43 N, 130À133 E). Enzootic JEV circulation without human morbidity has been documented, with the seroprevalence of residents estimated at about 10À20%. 11,18,29,30 JE cases occur mainly in AugustÀSeptember (but also when heavy rains are combined with high temperatures from April to September: $21 C in April, $23 C in June, $25 C in August, and $21 C in September).

Clinical Features. The clinical picture of JE varies from asymptomatic and easy feverish forms to an encephalitis syndrome. The ratio of clinical to asymptomatic forms is from 1:300 to 1:1,000, although the ratio in India in the 1970s and 1980s was from 1:20 to 1:30. 31À33

The start of the disease is sudden, with fever (80%), headache, vomiting (24%), and symptoms of CNS destruction (most often, hemiplegia and articulation lesions)-in 12% of cases, and at the height of the illness in 65% of cases. About one-third of patients with CNS lesions recover completely. 34 Lethal outcomes are preceded by unconsciousness and then coma (20À44% of the total number of patients). Death comes in two-thirds of cases during the first week, in one-fourth during the second week, and in the rest of the cases in one month, from the onset of symptoms. After the disease, residual phenomena in the form of paralysis and mental issues are quite often observed. 28, 32 Control and Prophylaxis. Inactivated vaccines are used to immunize people, 19,29,33,35À37 live vaccines to immunize pigs and horses. 31 Vaccination and protection of pigs from mosquito attack and protection of humans from mosquitoes (through the use of repellents, mosquito nets, bed curtains, etc.) are recommended during epidemics among people. Mass vaccination has been carried out successfully in Japan, South Korea, China, and India. 19,28,33,35À37 Live vaccine manufactured on the basis of the Chinese strain SA 14À22 is is given in China, South Korea, and other countries in government programs aimed at expanding immunization of children. 19 24 The complete genomes of TYUV and KAMV (GenBank ID: KF815939 and KF815940, respectively) were presented in a 1973 article in the Journal of Medical Entomology, 25 and it was established that KAMV was a new virus within the TYUV group of the Flavivirus genus.

Virion and Genome. TYUV is a prototypical virus of the Tyuleniy antigenic complex. The viruses of that complex belong to the ecological group of seabird tick-borne flaviviruses, which forms a distinct branch on the phylogenetic tree. 26 Four species are known in the Tyuleniy antigenic complex: TYUV (in Russia and the United States), MEAV (in Europe), SREV (in Oceania) and KAMV (in Russia). The genetic similarity between the seabird tick-borne flaviviruses and the mammalian tick-borne flaviviruses is about 42% nt. A full-length genome comparison showed that the similarity among the four viruses in the Tyuleniy antigenic complex is 70% nt and 85% aa, on average. TYUV LEIV-61C, isolated in the Russian Far East, has 86% nt and 97% aa identities with TYUV isolated on the Pacific coast of the United States. Kama virus (strain LEIV-Tat20776) has 70% nt identity with the other viruses of the Tyuleniy antigenic complex (MEAV, SREV, TYUV). The similarity of the polyprotein precursor of KAMV is 74% aa with each of TYUV and SREV, 78% aa with MEAV. 25 Arthropod Vectors. TYUV is distributed over the basins of the Sea of Okhotsk and the Bering and Barents Seas. The infection rate of Ixodes uriae in the Pacific part of the virus's distribution is 4.5 times greater than in the Atlantic part (Table 8 .31). 16 ,18À23 Outside of Northern Eurasia, TYUV is distributed over the west coasts of the United States (chiefly in Oregon) and Canada. 27, 28 The infection rate of nymphs and larvae of I. uriae is one-twentieth to one-half the infection rate of the imago. The infection rates of I. uriae females and males (the males have only a rudimentary hypostome and do not feed) are practically the same. 21 These data testify to the transphase and transovarial transmission of TYUV. (The efficiency of this type of transmission is about 5%.) Attempts to isolate TYUV from I. signatus ticks were unsuccessful.

The presence of antibodies to TYUV among local cows and indigenous people of the Commander Islands 19,21 indicates the possible role of sanguivorous mosquitoes (e.g., Aedes communis, Ae. punctor, and Ae. excrucians) in infection. Mosquitoes could also take part in virus circulation: Their infection rate from the end of July to the beginning of August reaches 0.3% in nesting colonies of seabirds and 0.1% on the seacoast.

Experimental infection of TYUV on the model of Aedes aegypti demonstrated the presence of the virus 4À31 days after inoculation, with 1.5À2.0 lg LD 50 /10 mcL on days 4À17; 3.0À3.5 lg LD 50 /10 mcL on days 23À27; and 1.5 lg LD 50 /10 mcL on day 31. The transmission of TYUV during the feeding of infected mosquitoes on mice was established 7À19 days after infection of the mosquitoes. In Culex pipiens molestus, TYUV was detected 5À21 days (the period of observation) after infection, with 1.0À2.0 lg LD 50 /10 mcL. 20 Vertebrate Hosts. Migratory seabirds play a role in the exchange of TYUV group flaviviruses between the Northern and Southern Hemispheres. 18, 29 Investigation with the help of indirect complement-binding reactions of sera samples from 2,500 birds collected in the Far East revealed that the maximum TYUV infection rate takes place in Brü nnich's guillemots (Uria lomvia), common murres (U. aalge), and tufted puffins (Fratercula cirrhata). Lower rates were seen in pelagic cormorants (Phalacrocorax pelagicus), redfaced cormorants (Ph. urile), glaucous-winged gulls (Larus glaucescens), kittiwakes (Rissa tridactyla), northern fulmars (Fulmarus glacialis), and sandpipers (Scolopacidae). 17, 18, 20, 21, 23, 30 The presence of specific anti-TYUV antibodies among sandpipers-red-necked phalaropes 27, 28, 31 Considering the annual migrations of these birds, TYUV can be found within the I. uriae area of distribution in nesting colonies of puffins. About 90% of adult and 10% of juvenile northern fur seals (Callorhinus ursinus) on the Commander Islands have specific anti-TYUV antibodies, implying that these animals are involved in the circulation of that virus. A TYUV strain was isolated from the Arctic ground squirrel (Citellus (Urocitellus) parryii) on the southeastern coast of the Chukotka Peninsula (63 N, 180 E). This event is one more argument for virus splash into the continent, with rodents included in virus circulation.

In the tundra of the Kola Peninsula seacoast, antibodies specific to TYUV were detected among cattle (28.1%) as well as red-necked phalaropes (Phalaropus lobatus), snow buntings (Plectrophenax nivalis), ruffs (Philomachus pugnax), and rodents: tundra voles (Microtus oeconomus). 21 Thus, in the Atlantic part of its distribution, TYUV also tends to penetrate into the continent.

Experimental infection of kittiwakes (Rissa tridactyla), herring gulls (Larus argentatus), and Brü nnich's guillemots (Uria lomvia) was followed by the development of clinical features with CNS lesions and lethal outcomes. 32 Epidemiology. The indigenous population in the Far Eastern part of TYUV distribution has specific anti-TYUV antibodies: 8.4% in tundra on the coast of the Chukotka Peninsular, 4.2% in forestÀtundra on the coasts of the Sea of Okhotsk and the Bering Sea, 7.4% -in taiga on Sakhalin island, and 9.1% in tundra on the coast of the Kola Peninsula. 21 The development of fever in humans visiting nesting colonies of seabirds on the coast of the Barents Sea has been described in the literature. 33 Ecological Peculiarities of TYUV and KAMV Distribution. Penetration of TYUV from the Northern to the Southern Hemisphere is carried out by about 20 species of birds, mostly turnstones (Arenaria interpres), that nest in the north of Asia and overwinter in Australia and New Zealand. Wedge-tailed shearwaters (Puffinus pacificus) nest in the Southern Hemisphere and carry out an annual migration along the coasts of the Pacific Ocean up to Northern Eurasia and North America. 23, 34 Close genetic relations found between TYUV and KAMV have not been explained yet because information is lacking about ecological links between Alcidae birds in the north and bank swallows in the central part of the Russian Plain. Nontheless, the closeness demonstrates an ancient link between the flaviviruses and Ixodidae ticks-obligatory parasites of colonial and burrow-shelter birds not only on the ocean coast, but also on the continental part of the distribution of those viruses. 19, 20, 23, 35, 36 MEAV and SREV, which are genetically close to TYUV, 25,26 could be intermediate evolutionary branches between tick-borne viruses of seabirds and later mammalian viruses transmitted by ticks. 13, 15 The main vector of TYUV in subarctic regions-Ixodes Uriae, adapted to seabirds-is replaced by the Ornithodoros capensis complex or Argas spp. in the subtropics and tropics. 18, 27 The northern boundary of the Argas genus distribution is limited by a July isotherm of 15À20 C and of the Ornithodoros genus by 20À25 C in Europe and 25À30 C in Asia. 37 The vector of KAMV-the I. lividus tick-has transpaleoarctic distribution, from the British Isles in the west to Japan in the east and from 62 N down to 43 S. This species of tick has an extrazonal distribution in the diggings of bank swallows (Riparia riparia) made in the soft ground of steeps along the banks of rivers and lakes in taiga, leaf forest, forestÀsteppe and 247 8.2 FAMILY FLAVIVIRIDAE steppe climatic belts. I. lividus ticks are typical parasites of-burrow-shelter birds and relate strictly to the life cycle of the host: After the appearance of birds in the nesting areas in May, larvae begin to feed. In June, nymphs feed on the nestlings; female imagoes also feed on the nestlings, but male imagoes do not. 38 Given the presence of KAMV-a virus closely related to TYUV-in the central part of the Russian Plain, it is worthwhile, and even necessary, to carry out a wider search for TYUV analogues on the continental part of Northern Eurasia.

History. Dengue fever (DENF), etiologically linked to Dengue virus (DENV) (family Flaviviridae, genus Flavivirus), has been known in Asia, Africa, and America since the end of the eighteenth century. 1,2 Wide epidemics of DENF appeared in southeastern Asia after World War II. 3 According to WHO data, DENF morbidity, including imported cases, has been detected in more than 100 countries of Asia, Africa, and Europe. More than 2.5 billion people on Earth are under the threat of DENF. About 50 million people fall victim to DENF annually. 4 American armies sustained heavy losses as the result of DENF during World War II, 3 as well as during 1960À1990 in Vietnam, the Philippines, Somalia, and Haiti. 5 Simultaneous outbreaks of DENF and Chikungunya fever often occur. 6 The virus etiology of DENF and its transmission by mosquitoes was established by P.M. Ashburn and C.F. Craig in experiments using volunteers at the beginning of the twentieth century. 7 DENV-1 was isolated in 1944 from the blood of patients with fever on the Hawaiian Islands, 8 DENV-2 in 1944 from the blood of patients with fever on New Guinea, 8 DENV-3 in 1956 from the blood of patients with fever in the Philippines, 9 and DENV-4 in 1956 from the blood of patient with fever during epidemics in Manila. 9 Taxonomy. Four different serotypes of DENV form a distinct phylogenetic lineage on the mosquito-borne flavivirus lineage (Figure 8.47 ). Genetic variation among different strains suggested that DENV be divided into distinct genetic clusters considered as genotypes. The genetic diversity of DENV is best exemplified in DENV-2, the different strains of which are divided into four genotypes: Asian 1, Asian 2, American/Asian and so-called Cosmopolitan. 10 DENV-3 strains are divided into five genotypes (IÀV), 11 and DENV-4 strains form three genotypes. 12 In general, a particular genotype is linked to specific geographical regions and that genotype may be used in describing imported cases of DENV infection.

Arthropod Vectors. DENF belongs to natural-foci diseases. Its vectors are anthropophilic species of mosquitoes: Aedes aegypti and Ae. albopictus in synantropic natural foci. Humans are the only vertebrate hosts in synantropic natural foci, whereas wild mammals are involved in virus circulation in sylvatic natural foci. Vectors in equatorial Africa are Ae. furcifer, Ae. vittatus, Ae. tailori, and Ae. luteocephalus.

Vertebrate Hosts. In southastern Asia, the vertebrate hosts of DENV are macaques (genus Macaca) and surilis (genus Presbytis) living in the rain forests of equatorial climatic belts; the main vector is Aedes niveus; a circulation of DENV-{1, 2, 4} has been identified. Natural foci of DENV were also found in the eastern part of equatorial Africa, in Senegal and Nigeria. The vertebrate hosts are patas monkeys (Erythrocebus patas); wild strains are considered possible precursors of epidemic ones. Among humans, wild strains provoke slight clinical forms of Dengue fever. 13À15 Epidemiology. DENF has an epidemic character involving tens of thousands of people in southeastern Asia, Oceania, the Caribbean basin, Central and South America, and Africa. The transmission pathway is a mosquito bite, mainly by members of the Aedes genus. These mosquitoes are able to transmit DENV in 8À10 days after feeding on a sick person. About 60À70% of the human population falls victim to DENF during epidemics. 15 DENV continues to circulate actively and to provoke wide epidemics. For example, all four types of DENV exist in Sri Lanka, with new clades replacing old ones, accompanied by a severe clinical picture. 16, 17 In the 1980s, a new wave of DENF epidemics began to develop in Sri Lanka, India, Pakistan, and Central and South America. 18, 19 These epidemics were linked mainly to the relatively new DENV-3, but to DENV-1 and DENV-2 as well. 20 In some cases-for instance, in Myanmar 21 and China 1 -all four types of DENV circulated simultaneously.

Clinical Features. The incubation period is 2À7 days. The start of the disease is quick, with fever and with frontal and retroorbital headache. Lymphadenopathia, rash in macule and papule forms (not always), leukopenia, skin hyperesthesia, changes in taste, loss of appetite, and muscle and joint pains gradually develop. Then, after 1À2 days of normal body temperature, the second wave of fever develops, accompanied by a measleslike rash. The palms and soles are rash free. Severe CNS complications have been described to arise in endemic regions (e.g., Brazil). 3 The hemorrhagic clinical form of DENF, with shock and a high level of lethality (especially among children), was originally seen in the Philippines in 1953. Later, this clinical form was registered in India, Malaysia, Singapore, Indonesia, Vietnam, Cambodia, and Sri Lanka, as well as on islands in the Pacific. According to WHO data, more than 1.3 million patients had hemorrhagic DENF from 1956 to 1992, with 14,000 lethal outcomes. Starting from 1975, hemorrhagic DENF has become the main cause of hospitalization and deaths among children in the countries of southeastern Asia. 1 The hemorrhagic form of DENF usually develops after a secondary infection by a type of DENV different from the primary one. The primary type of DENV is not neutralized, but fragments antigen binding (Fab)associated enhancement of the infection occurs. For example, in French Polynesia in 2000, two years after epidemics of DENV-2, an outbreak etiologically linked to DENV-1 emerged and hemorrhagic DENF was detected among children 6À10 months and 4À11 years old. 16 Five symptoms are characteristic of the hemorrhagic clinical form of dengue: high temperature, rash, hemorrhagia, hepatomegalia, and insults to the circulatory system. Thrombocytopenia with blood condensation also occurs. 4 Hemorrhagic DENF can be without shock or can precede it. Shock develops in 3À7 days of the disease, wheninsults to the circulatory system appear: The skin becomes cold, sticky, and cyanochroic; the pulse rate increases; and drowsiness appears. In the absence of antishock actions, patients die within 12À24 h. The severity of the disease depends on a number of factors: the infection titer in the blood, the type of DENV, its biological properties, and more. 22À24 Imported Cases of Dengue. There is a high risk of DENV infection for visitors to endemic regions, with consequent penetration of the virus into nonendemic regions. 1, 25 DENF has occurred in Spain in the past (e.g., in Cádiz in 1778). Several tens of human cases are introduced into the country each year from equatorial and subequatorial regions. DENV-1 and DENV-2 caused a huge outbreak in Greece in AugustÀSeptember of both 1927 and 1928: in those periods, about 650,000 of 700,000 inhabitants of Athens and Piraeus contracted DENF, including hemorrhagic forms and about 1,000 lethal outcomes. 26 Penetrations of DENV also took place in the Netherlands in 2006À2007 27 and in Japan, 28 France, 29 northern Italy, 30 and Germany in 2010. 31 During 2002À2011 in Russia, among patients with fever from the risk group that visited tropicalÀequatorial countries, 48 cases of DENF were identified with the help of serological investigation (22 cases arrived from Indonesia; 11 from Thailand; 3 each from Vietnam and India; 2 each from Venezuela and the Dominican Republic; and 1 each from Sri Lanka, Malaysia, Singapore, Sierra Leone, and Costa Rica). 32À34 In 2013 in Russia, 30 cases of DENF were identified in Moscow, 8 in St. Petersburg, and 8 imported strains of DENV were isolated.

The risk of DENF for Europe has appeared again with the introduction of Aedes albopictus and Ae. aegypti mosquitoes in the countries of the Mediterranean and Black Sea basins. 35 Stable populations of both these species were found on the southeastern coast of the Black Sea (in Krasnodar Krai, Russia, as well as in Abkhazia). 36À38 Control and Prophylaxis. The main approach to prophylaxis is to struggle against mosquito vectors. During the 1950s and 1960s, a program against Ae. aegypti mosquitoes that was unprecedented in terms of scale and expense was conducted in America, but it was stopped in 1970; as a result, in 1995 the number of Ae. aegypti mosquitoes was estimated to be same as that before the program began. 39 The struggle against mosquito vectors in Singapore turned out to be more successful, but still did not prevent DENF morbidity. 40 Investigations into four-component vaccines are far from completion today. 22, 41 Express methods of DENF diagnostics are used in airports. 42 WHO issues a reference guide for the diagnosis, treatment, prophylaxis, and control of DENF. 43 (Table 8 .32, Figure 8 .60). Further serological investigations with the help of HIT revealed that SOKV belongs to the Flaviviridae family, and with the help of complement-fixation testing (but not neutralization testing), to the Entebbe bat serogroup. 1À3 A prototypical strain of this serogroup was isolated from a Kenyan big-eared free-tailed bat (Tadarida lobata) collected near Entebbe, Uganda, in July 1957. 5 Taxonomy. The genome of SOKV was sequenced, and genome analysis showed that the virus is related most closely (71% nt and 79% aa identities) to Entebbe bat virus (ENTV). SOKV has about 50% nt and 55% aa identities with other flaviviruses, except viruses of the Rio Bravo (RBV) and Modoc (MODV) groups (,50% similarity). 6 No arthropod vector of ENTV and SOKV has been established; however, phylogenetic analysis based on a full-length genome comparison placed SOKV and ENTV together on a distinct branch of mosquito-borne flaviviruses related to YFV and Sepik virus (SEPV) (Figure 8.47) .

Arthropod Vectors. According to serological data, domestic animals do not take part significantly in SOKV circulation, although antibodies to SOKV were detected among cows and sheep. Isolation of SOKV from birds that were known not to have made contact with obligatory parasites of bats, as well as the presence of positive sera from humans and domestic animals, suggest the participation of mosquitoes in SOKV circulation. Transmission of the virus by bats could be carried out by Argas vespertilionis and Ixodes vespertilionis. 7À10 Vertebrate Hosts. More than 20 flaviviruses were isolated from bats (order Chiroptera); about half are unique to these mammals. 11 24 ; and Yokose virus (YOKV). 25 The insectivorous bats Vespertilio pipistrellus, from which SOKV was isolated, belong to the evening bats family (Vespertilionidae), which is active during the evening and at night. Their daylight shelters are situated mostly in house garrets. V. pipistrellus is distributed over Europe, the Mediterranean, the Caucasus region, and central Asia. A part of the population overwinters in Africa, where infection by local viruses (e.g., BBV, DBV, ENTV) could occur.

Experimental infection of sparrows (Passer montanus) resulted in SOKV being detected in internal parts of infected birds on the 8th and 25th days after inoculation. 26 Epidemiology. There are no laboratoryconfirmed human cases of SOKV infection. Nevertheless, the proximity of SOKV hosts (bats) to human habitats, as well as the presence of encephalitis and hemorrhagic fever agents among the flaviviruses, suggest that SOKV may be dangerous to humans.

Complement-binding specific anti-SOKV antibodies were detected among humans in Kyrgyzstan and Turkmenistan (6.2% and 4.0%, respectively), testifying to recent infection events. 1À4,7,9,10,16,27À31

History. WNV (family Flaviviridae, genus Flavivirus), theetiological agent of West Nile fever (WNF), was first isolated during research on YFV in 1937 from the blood of a native of Uganda who was suffering a mild fever. 1 The strain isolated, B956, belongs to genetic lineage II. (See "Taxonomy" next.) Strain Eg101, isolated from the sera of a child without clinical signs in Egypt, 2 is the prototype for African genetic lineage I, widely used for investigations. WNV belongs to the JEV group, has the broadest antigenic properties, and, on theoretical grounds, appears to be the most ancient member of the Flavivirus genus. 3 Lowpassaged WNV strains are known by many investigators to be common causes of laboratory infection, apparent or inapparent. 4 Taxonomy. Phylogenetic analysis revealed that different geographic isolates of WNV could be grouped into two major genetic lineages (Figure 8.61 ). Lineage I includes strains from Africa, southern and eastern Europe, India, and the Middle East. Lineage II includes isolates from west, central, and east Africa, as well as Madagascar. Lineage 1 can be subdivided into three clades: Clade 1a consists of strains from Europe, Africa, the United States, and Israel. The topotypic isolates of WNV in Australia-Kunjin virus (KUNV)belong to clade 1b, and clade 1c is formed by isolates from India. 5 Subsequently, two genetically divergent Rabensburg strains-97À103 (isolated in the Czech Republic) and LEIV-Krnd88-190 (isolated in Russia)-were proposed to form novel lineages III and IV, respectively. 6À8 A fifth lineage was formed by strains from India. 9 Phylogenetic analyses based on complete genomic sequences revealed that the various lineages differed from each other by 20À25%. A putative novel sixth lineage has been detected in Spain in 2006, but only a partial sequence of the NS5 gene of this isolate is available in GenBank. 10 World Distribution. The distribution of WNV in Northern Eurasia, and indeed, in the whole world, covers vast territories within the equatorial, tropical, and temperate (the southern part) climatic belts in Africa, Europe, Asia, Australia, and North America (the last starting from 1999).

In Africa, it is very difficult to find a country or landscape in which WNV has not been detected by either a virological or serological approach. The isolation of this virus from a wide array of species of birds, mosquitoes, Ixodidae and Argasidae ticks, and domestic animals as well as humans testifies to the ecological plasticity of the virus and therefore to its ability to adapt to different ecological conditions. Two genetic lineages circulate in Africa: the first, which dominates, and the second.

Sporadic morbidity and epidemic outbreaks permanently take place in a number of African countries, especially the Republic of South Africa, where a wide outbreak with at least 3,000 human cases occurred in 1974 after an active period of rain. According to a report from the Pasteur Institute, during the last 10À15 years alone, epidemic outbreaks were registered in Algeria (in 1994, with more than 50 cases and 8 deaths, and in 1997, with 173 cases), in Tunisia (during 1997À2003, with 173 cases), Morocco (in 1996 and 2002; the epidemic reached both humans and horses), in Senegal (in 1993), and in Kenya (in 1998). 11 New centers of infection continue to be arise in Africa-for example, in 2009 in Morocco, where morbidity among people and horses was observed and 3.5% of birds had specific anti-WNV antibodies, 12 and in 2010 in the Republic of South Africa, where there were a number of lethal outcomes. 13 The wide distribution of WNV in Africa and its circulation among populations of the majority of the continent's species of local and migrating birds indicates that the virus is able to penetrate to southern Europe and western Siberia through the birds' migration pathways. Most of the birds nesting in or migrating through the Volga delta overwinter in Africa. 14 Thus, Africa is the main source of penetration of WNV genotypes I and II into southern Europe and western Siberia.

In Asia, a peculiar third genotype of WNV appears to be circulating in the Indian subcontinent. 11 A prototypical strain of WNV genotype 3 was isolated from xCulex vishnui mosquitoes in southeastern India, and human morbidity was identified in India, Pakistan, and Israel. Taking into account the fact that most of the birds from western Siberia and many from eastern Siberia overwinter in India and other countries of southern Asia, there is a high probability that WNV genotype 3 has penetrated into Siberia. Also in Asia, both epidemics and sporadic cases etiologically linked with the first genotype of WNV have arisen regularly in Israel since at least1958. One such outbreak was observed in 1999À2000. 15 Surveillance in South Korea does not indicate any WNV circulation in that country. 16 In Australia and Oceania, the Kunjin variant of the first genotype of WNV appears to be circulating. 17À19 KUNV could be introduced into Northern Eurasia (in eastern Siberia and the Far East) by migrating birds overwintering in southeastern Asia and Australia. 11, 14 In 2011, an outbreak among horses in New South Wales, Australia, was identified. 20 In central Europe, for a long time only two strains of WNV were known: one isolated in from Aedes cantans in 1972 in western Slovakia and the other isolated from Ae. vexans, Ae. cinereus, and Culex pipiens in 1997 in the Czech Republic, near the Austrian border. Anti-WNV antibodies were identified in the Czech Republic among 1.4À9.7% of birds, including crows, daws, turtle doves, common kestrels, ducks, coots, and thrushes. Later, two strains of the so-called Rabensburg genotype of WNV were isolated from Cx. pipiens in 1997 and 1999 in the Czech Republic. 21À23 The strain belonging to the second lineage of WNV was isolated from a goshawk in Hungary. 7 In 1996 in Tuscany, Italy, Usutu virus (USUV), which is closely related to WNV, was isolated during an epizootic episode among birds, especially thrushes (Turdus merula), and then, again, in 2001 in Austria. Later, this virus was found in Hungary, Switzerland, and Germany. 24 Practically all of the southern European countries are endemic for WNV. 25, 26 Especially tragic events unfolded in Romania, where there was an epidemic in JulyÀOctober 1996 with a peak at the end of August to the beginning of September in the southeastern part of the country, downstream of the Danube River. Six administrative units and Bucharest were affected, among other jurisdictions. Human morbidity reached 12.4%, and 835 patients with CNS insult were hospitalized. The number of patients with fever was at least 10 times more, and the number of infected individuals 100À300 times more. The outbreak, which dragged on until 2000, 27 testifies to the development of a city epidemic form of WNF. The virus belonged to the first genotype of WNV and probably was brought to Romania by birds from Africa.

WNV distribution in Europe indicates an especially high risk of a WVF outbreak in deltas of the large rivers-the Rhô ne in France and the Danube in Romania-through which the main migratory paths of birds overwintering in Africa lie. 14 In the recent past, WNV has been active in Europe in Italy, 28, 29 Greece, 30, 31 Spain, 10 Poland, 26 the Czech Republic, 3, 22 and France. 22 Infected mosquitoes were imported into Great Britain from the United States by airplane travel. 32 As for North America, before 1999 that continent was free of WNV. Penetration of WNV into America most likely happened by infected mosquitoes in the holds of ships from ports in the Mediterranean Sea or Black Sea. 11 Fifty-six cases of human WNF were revealed in New York City and its surroundings at the end of JulyÀSeptember 1999, with a peak in the second half of August. Seven cases (12.5%) had a lethal outcome. The virus was found in Culex sp. and Aedes vexans mosquitoes caught in SeptemberÀOctober in New York City and in the states of New Jersey and Connecticut. Positive results were obtained by RT-PCR during an investigation of brain tissues of dead birds: crows, seagulls, storks, herons, ducks, cuckoos, pigeons, jays, robins, hawks, and eagles. The genomes of the strains that were isolated were found to belong to the first genotype and were close to the strains isolated in 1996 in Romania and in 1998 in Israel. 33 In 1999, WNV was registered in the United States, probably translocated there by migrating birds or by infected mosquitoes inhabiting the holds of visiting ships. WNV was found in By 2003À2004, practically all the territory of the United States, southern Canada, and Latin America became endemic with high morbidity and mortality. 34 The greatest morbidity in the United States was found in the states of NorthDakota, South Dakota, and Nebraska. 27, 35 The number of diseased individuals reached 4,000À9,000 cases in separate years. During 1999À2006 in the United States, more than 16,000 WNF cases were identified, with more than 600 (4%) succumbing to the disease. The economic damage was estimated in billions of dollars. 36, 37 Today, WNV continues to circulate in the United States. 38, 39 Morbidity grew in the states of Louisiana and Mississippi after Hurricane Katrina. 40 In Montana, the infection rate of people living in close proximity to a colony of pelicans (Pelecanus erythrorhynchos) is five times higher than in other regions of the state. 41 In a sea park in Texas, grampuses (Orcinus orca) contracted encephalitis and died, 42 and previous episodes of polyencephalomyelitis were revealed among seals (Phoca vitulina). Also in Texas, three new genetic clades of WNV were found, testifying to rapid evolution of the virus on the American continent. 43 In 2012, an epidemic arose again, accompanied by a large number of lethal outcomes. In Texas, a state of emergency was declared.

Northern Eurasia. In Northern Eurasia, on the basis of the results of multiple investigations, the distribution of WNV includes Moldova, Ukraine, Belarus, Armenia, Azerbaijan, Georgia, Kazakhstan, Tajikistan, Kyrgyzstan, Uzbekistan, Turkmenistan, the south of the European part of Russia (the desert, semidesert, steppe, and forestÀsteppe landscape belts), and western Siberia. 11, 35, 44 The first data on WNV isolation were obtained from Hyalomma marginatum ticks collected in the Astrakhan region in 1963. Data were also obtained in Azerbaijan from a blackbird (Turdus merula) and a European nuthatch (Sitta europaea) and, later, from a herring gull (Larus argentatus) and Argasidae ticks (Ornithodoros coniceps) parasitizing it. 14 WNF morbidity is now a permanent feature in the Astrakhan region, Kazakhstan, central Asian countries (republics of the former USSR), Ukraine, and Azerbaijan.

Virological, entomological, zoologicoornithological, and epidemiological investigations of WNV in the Astrakhan region and the Kalmyk Republic were conducted especially actively. 8,39,45À61 Virus activity in the Volga River delta was found at least as far as 50 years ago. 11, 35, 60 But interactions between WNV, on the one hand, and animal and vector populations, on the other, were not investigated in detail as well as genetic characteristics of the virus; indeed, the latter began to be studied well only during the first decade of twenty-first century, when suckling mice and Vero-E6 cell culture were used to isolate the virus and serological investigations were employed to detect viral RNA (neutralization testing, ELISA, HIT) and to sequence genes (RT-PCR).

WNV endemic territories in southern Russia were known from the moment the virus was isolated in the Astrakhan region in 1964. (The number of cases confirmed by ELISA in the southof the European part of Russia is presented in Table 8 .33.) Sporadic cases with a moderate clinical picture and minor outbreaks were observed in the area practically annually, as well as in other southern regions of the former Soviet Union. The immune structure to WNV among humans in the USSR was also known, with the most immunity occurring in the south of Russia, mainly the Astrakhan region (Figure 8 .62, Table 8 .34).

All this familiarity with WNF is why an outbreak in 1999 in Volgograd was not exactly unexpected, 62 even though it originally was identified by regional experts as an enterovirus infection. Still, laboratory-confirmed WNF cases reached more than 500 that year, and according to our estimations, the number of infected patients exceeded 200,000 (Table 8.35) . Mortality (about 10%) was also unusually high. Large deltas of European rivers such as the Rhô ne, Danube, and Volga Rivers are known to be transit hubs for migrating birds and places of introduction of viruses linked with birds. 14 The main natural focus in Russia is the Volga delta.

The Volga delta and contiguous territories around the northern Caspian basin have been endemic for WNF for many years (Tables 8.33À8 . 35) , and other arboviruses have been ecologically linked with aquatic and semiaquatic birds frequenting the region. Ninety percent of these species of birds overwinter on the African continent. Up to 100,000 birds pass over the region daily during their seasonal migrations via the Volga delta main line of the eastern Europe migratory route.

(See Figure 3.2 .) The problem is that the Volga delta is the place from which viruses are introduced into anthropogenic biocenoses in close vicinity to human habitation. One consequence of this scenario was epidemic outbreaks in the Astrakhan and Volgograd regions in 1999À2001.

The Volga delta consists of three basic belts, each with its own unique ecosystem features (Figure 8.63) .

The lower Volga delta borders the Caspian Sea and is characterized by extensive exposed spaces with water. The water depth usually does not exceed 1.0À1.5 m, a situation that is highly conducive to the mass propagation of mosquitoes and one that also provides nesting opportunities for aquatic and semiaquatic birds. Near where it empties into the Caspian Sea, the Volga bed turns significantly to the west, so the western part of the delta, including both the reed bed of the northwestern Caspian coast (up to Lagan in the Kalmyk Republic) and some flooded islands, is more extensive than the central and eastern parts. The extreme eastern part of the delta lies in Kazakhstan. A number of hunters and fishermen could be infected in the lower delta of the Volga. The middle Volga delta is more distant from the sea, has powerful currents, and consists of shallow lake ecosystems with reeds and shrubs. Water ecosystems adjoin semidesert ones. Within the limits of this zone, wild biocenoses combine with anthropogenic areas around a number of settlements, whose inhabitants keep cattle, sheep, and camels. WNF is widely registered among the native population.

The upper Volga delta adjoins the VolgaÀ Akhtuba lowlands and semideserts. Large cities, including Astrakhan, are located within the limits of this zone. Some species of wild birds that are common in the middle delta also occur in this zone, coming into close contact with domestic animals and synanthropic birds.

Analysis of retrospective data collected before 1999 revealed that the main locus of native-population morbidity by WNF is in the Volga delta (Table 8 .35). Viruses could be introduced into the northern part of the VolgaÀAkhtuba lowland up to Volgograd and maybe even higher. Thus, in the future it will be necessary to control the introduction of the virus into the VolgaÀAkhtuba lowland from Astrakhan to Volgograd.

Arid landscapes occupying contiguous terrian to the west of the VolgaÀAkhtuba system and the Volga delta are situated within the boundaries of the Caspian SeaÀTuranian Basin physicogeographical area (Figure 8.63) .

Every year at the end of July, a group of specialists from the D.I. Ivanovsky Institute of Virology in Moscow has traveled to the Astrakhan region and the Kalmyk Republic to organize and conduct a joint scientific expedition with local Centers of SanitaryÀEpidemiological Inspection for ecologo-virological monitoring of the northwestern Caspian region (Figures 8.64À8.66) . The main goal of the expedition is to contain the ecological and epidemiological situation after suppression of WNV circulation in the previous epidemiological season as the result of a combination of natural factors.

The plan for the collection of field material took into account the results of previous expeditions, when key milestones and marker species of mosquitoes and wild and domestic animals were identified. In particular, the researchers planned to investigate the role of the Ixodidae tick Hyalomma marginatum (Figure 8 .67) in WNV and other arbovirus circulation in anthropogenic and wild biotopes.

Both federal and local heads of various services, as well as virologists, epidemiologists, veterinarians, hunters, and frontier guards, were supplied with materials containing evaluations of ecologo-virological monitoring of their respective territories in the previous epidemiological season. Practical recommendations were given for prophylaxis of WNF, CCHF, and other arboviral diseases.

Field materials-bloodsucking mosquitoes, Ixodidae ticks, internals (blood, serum, liver, spleen, and brain) of wild birds and mammals, and sera from donors and domestic animalswere collected on the territory of the Astrakhan region and the Kalmyk Republic from the end of July to the beginning of August 2000À2004 within the boundaries of the Volga delta, the VolgaÀAkhtuba valley, and adjacent arid landscapes. Field materials were collected in the biotopes of the west Volga coast and the east Akhtuba coast, including internal waterÀmeadows of the upper and lower VolgaÀAkhtuba zones, hydromorphic and adjacent meadowÀsteppe biotopes of the upper and meddle belts of the Volga, the Volga avandelta, the territory of the Sarpa Lakes, and the east side of Ergeny (see Figures 8.64À8.66 ).

During 2000À2004, the expedition collected 504,731 bloodsucking mosquitoes (of the order Diptera and family Culicidae: genera Culex, Aedes, Coquillettidia, and Anopheles); 11,266 Ixodidae ticks (of the taxon Acari and family Ixodidae: genera Hyalomma, Rhipicephalus, and Dermacentor), mainly H. marginatum; internal parts of 2,794 birds and 67 hares (Lepus europaeus); sera from 4,500 human donors (2,500 in the Astrakhan region and 2,000 in the Kalmyk Republic); and sera from 5,300 domestic animals (2,900 in the Astrakhan region and 2,400 in the Kalmyk Republic) (Figure 8.68 ).

The field materials that were collected were stored and transported to the D.I. Ivanovsky Institute of Virology in liquid nitrogen in dewars, in accordance with all requirements for the handling and transport of infectious samples.

Internal parts of 2,794 wild birds were investigated by virological methods (Table 8 .36). Twelve WNV strains (Tables 8.36 and 8.37) were isolated. According to the bioprobe method used, the total WNV infection rate among wild birds is about 0.4%, with the highest level (0.7%) reached in the middle and RT-PCR testing for any indication of WNV RNA was carried out on 108 samples of internal parts collected from wild mammals on the territory of the northwestern Caspian region. Positive results are presented in Tables 8.42 detected in Anopheles messeae (0.028%), a common visitor to houses with domestic animals in anthropogenic biocenoses, as well as in An. hyrcanus (0.026%) in rushes in natural biocenoses. As is illustrated in Figure 8 .73, the highest intensity of WNV circulation takes place among sanguivorous mosquito populations in anthropogenic biocenoses on the territory of the Volga delta (Figure 8.74 ). RT-PCR testing was carried out for the detection of WNV RNA in 11,266 samples of Hyalomma marginatum ticks (taxon Acari, WNF cases began to be registered starting in June 2001, with the maximum reached in August (Figure 8.76) . Durint the first three 27 .0% of patients in the latter group had intracranial hypertension syndrome. There were two cases of severe disease: a 71-year-old patient with seromeningitis and an 8-year-old child with neurotoxic syndrome during the acute period. All of the cases had a favorable result: No lethal cases were registered.

Sera from 2,884 farm animals collected in the Astrakhan region during 2001À2004 were tested by HIT and neutralization testing in order to detect specific anti-WNV antibodies. In addition, HIT-positive sera underwent neutralization testing. Anti-WNV antibodies were found by HIT in all species investigated: horses (mean positive result for the entire observation period, 9.8%; coincidence with neutralization testing, 94.1%), cattle (6.4%; 72.0%), camels (5.2%; 41.7%), pigs (3.1%; Cattle are the main host of Anopheles messeae, and cowsheds offer favorable conditions for the mosquitoes to reproduce. Cattle-specific antigens could often be found in the intestines of Culex pipiens females (but not An. Messeae females), which inhabitat damp basements. Town utilities adjoin with farm utilities in all settlements of the Astrakhan region, so cattle are the hosts both for An. messeae and for Cx. pipiens. Both species of mosquitoes are active vectors of WNV in anthropogenic biocenoses.

Horses were the only species of farm animals with clinically expressed WNF. In contrast to cattle, whose pastures are situated close to human settlements, horses browse far from settlements, often grazing in natural biocenoses. A significant portion of horse livestock in the Astrakhan region are of the Kushum breed, bred for meat and racing, and browse freely all year. Pedigree horses (Don, Akhaltekinsky and Arabian race horses) are kept in bloodstock farms in a stall, or they browse locally. Draft horses are kept in settlements. Horse-specific antigens have been found in the intestines of replete females of all mosquitoes species (except for Culiseta annulata, which are relatively fewer). The total (2001À2004) distribution of HITpositive horses increases from the upper VolgaÀAkhtuba to the lower, with the highest number found in the middle belt of the Volga delta (where the epicenter of the natural foci is located).

Pigs are the animals closest to human settlements, so pig-specific antigens are often found in the intestines of replete females of the anthropogenic mosquito species Anopheles messeae and Culex pipiens. Pigs are kept in individual yards or on pig farms. The latter are situated far from human settlements. As they are in cattle housing, An. messeae are the main mosquito species on the pig farm; nevertheless, all mosquitoes collected here by probe were negative for WNV. In 2003, we collected sera on the pig farms, and all probes were HIT negative. In 2004, we collected sera both on pig farms and in individual yards.

Sheep are the most numerous species of farm animal in the Astrakhan region. Sheep pastures are in the dry steppe, where conditions are favorable for the Ixodidae tick Hyalomma marginatum. Only a couple of species of mosquito could live in the saltish, dry steppe il'mens: Aedes caspius and Cx. modestus. The latter is an active vector for WNV. A stable and low level of infection rate among sheep (about 2%) reflects the low level of intensity of WNV circulation in arid landscapes of the Astrakhan region.

Kalmyk racing camels inhabit more arid landscapes than sheep inhabit; consequently, one might expect a lower level of seropositive camels. However, HIT often demonstrates a high percentage of positive results: 33.3% in 1989 and 13.9% in 2001. So, we instead collected sera from camels during 2002À2004 in semiwild pastures, and the percentage of seropositive results decreased. The coincidence between the results of HIT testing and neutralization testing is presented in Table 8 .46. Horses are the best marker of WNV circulation, because they have the largest percentage of HIT-positive results and the greatest coincidence between HIT and NT results. Kushum race horses are the most significant marker. Monitoring the infection rates among farm animals will be continued, taking into account the relationships and phenomena described.

It has been found that WNV can remain viable during interepidemiological periods in overwintering imagoes of sanguivorous mosquitoes (e.g., Anopheles messeae, Culex pipiens and Culiseta annulata) as well as overwintering imagoes of the Ixodidae tick Hyalomma marginatum. The scheme of WNV circulation on the territory of the northwestern Caspian region is presented in Figure 8 .77.

After the 1999À2006 outbreak of WNF in four administrative units in southern Russia, a significant outbreak with more than 500 cases arose in the summer and autumn of 2010. The disease spread up to 500 km to the north and northeast from an earlier known endemic area and now includes an additional two administrative units (Tables 8.47 

The Orthomyxoviridae includes six genera of enveloped viruses with a segmented, negative-polarity ssRNA genome. The genome of the orthomyxoviruses consists of six (Thogotovirus and Quaranjavirus), seven (Influenza C virus), or eight (Influenza A virus, Influenza B virus and Isavirus) segments. 1,2 All orthomyxoviruses encode three enzymes formed of viral RdRp: PB1 (Figure 8.79) , PB2, and PA. These proteins are about 30% similar among viruses of different genera. Common structural proteins are NP, associated with genomic RNA; matrix protein; and two envelope proteins: hemagglutinin, or HA (possesses hemagglutinating activity) and neuraminidase, or NA (also called sialidase) in the influenza viruses.

Viruses of the Thogotovirus and Quaranjavirus genera are transmitted by arthropod vectors, predominantly Ixodidae and Argasidae ticks, respectively. Viruses of the Influenza A virus, Influenza B virus and Influenza C virus genera are important human pathogens transmitted by a respiratory route. 1 Genus Isavirus has only one species: infectious salmon anemia virus, which strikes fish in the Salmonidae family.

Genus Influenza A virus has just one named species: Influenza A virus, represented by numerous antigenic and genetic subtypes. The genome of Influenza A virus consists of 8 segments of ssRNA that encode 11 or more proteins. 1À5 Influenza A viruses are divided into distinct subtypes based on the antigenic and genetic properties of their HA and NA proteins. Sixteen subtypes of HA (HA1À16) and 9 subtypes of NA (NA1À9) have been found worldwide in aquatic birds. Two additional subtypes of HA (HA17 and HA18) and NA (NA10 and NA11) are seen in New World bats. 4,6,7 H17 and HA18 form a clade distinctly 

History. Influenza as a human disease was originally described in 412 B.C. by Hippocrates (Figure 8 .82) in his book Epidemics, but the "father of medicine" did not consider influenza to be an infectious disease. Instead, the famous English physician Thomas Sydenham (Figure 8.83 ) was the first who suggested the infectious nature of the disease. 1, 2 The term "influenza" has been around since the first half of eighteenth century and derives from the Italian "influenza di freddo" ("influence of the cold") or from Spanish "influencia de las estrellas" ("influence of the stars"), the latter reflecting the contemporaneous belief in astrological reasons for the emergence of disease. 3 Up to the nineteenth century, the archaic terms "catarrhus epidemicus," "cephalgia contagiosa," "febris catarrhalis" and "febris comatose" had wide currency. 4 The English word "grippe" (related to the Russian "грипп") is related to the German "greifen" ("to catch hold") and derived from the French "gripper" ("to catch hold," "paralyze"); the word gained currency at the beginning of nineteenth century. (Cf., e.g., the passage from Volume 1, Chapter 1 of Tolstoy's famous novel War and Peace: "She was, as she said, suffering from la grippe; grippe being then a new word in St. Petersburg, used only by the elite."). 5 Before the nineteenth century, influenza A epidemics were described only qualitatively.

Subtypes of the etiological agent were retrospectively revealed for the 1889À1892 epidemic (H2N2), the 1897À1900 epidemic (H3N8), and the 1918À1919 pandemic (H1N1, the so-called Spanish flu) 5À9 -retrospectively only because Influenza A virus wasn't found until 1930 by Richard Shope (Figure 8 .84) on the model of swine (Sus scrofa) flu. 10, 11 Human flu was found two years later 12,13 by a group of English scientists: Wilson Smith (Figure 8 .85), Christopher Andrewes (Figure 8 .86) and Patrick Laidlaw (Figure 8.87) . During the pandemic of 1918À1919, it was suggested that the etiological agent of influenza A was the socalled AfanasievÀPfeiffer bacillus," 14À16 named after the Russian bacteriologist Mikhail Afanasiev (Figure 8 .88) and the German bacteriologist Richard Pfeiffer (Figure 8 .89)-the modern Haemophilus influenzae bacillus. 17, 18 Three Influenza A pandemics were described after the discovery of the etiological agent: the Avian flu has been known under the name "Lombardian disease" since the beginning of the nineteenth century. 31À34 In 1878, the Italian veterinarian Edoardo Perroncito (Figure 8 .90) described a highly contagious disease (previously named "exsudative typhus of chickens") among chickens, with 100% lethality in the vicinity of Turin. 35 The terms "classic fowl plague" and "bird pest" came into wide use in 1901, when a large epizootic outbreak in Tyrol province, Italy, did away with the population of farm birds there. 33 The term "Braunschweig disease" was used to identify an analogous disease among guinea fowls in Europe.

In 1901, the Italian scientists Eugenio Centanni and Ezio Savonuzzi demonstrated that the etiological agent of classic fowl plague is a filtrated substance. 34 Nevertheless, classic fowl plague wasn't identified as Influenza A virus until 1955, by Werner Shäfer (Figure 8 .91) on the example of the historical strain A/chicken/Brescia/1/1902 (H7N7). 36, 37 W.B. Becker was the first who identified Influenza A virus among wild birds when he Subtypes of Influenza A Virus in Northern Eurasia. At present, we know that numerous avian influenza viruses are abundant in the bird populations of Northern Eurasia. However, until the end of the 1960s, these data were absent. At that time in the former USSR, avian Influenza A virus was being isolated only from poultry. One of the first avian viruses isolated in the USSR-A/duck/Ukraine/1/1963-was destined to play an important role in the development of the theory of influenza virus evolution. 43 In 1960À1964, a group of researchers in the Ukrainian Soviet Republic isolated several influenza virus strains from ducklings affected with sinusitis. The first three strains were isolated in 1960 in Crimea and in the Kharkov Astrakhan region  95 24  49  31  11  25  73  16  1  1  5  22  18  67  70  508   Volgograd region  380 32  15  15  3  12  63  2  5  411  57 Institute of Virology in Moscow. As early as 1964, the duck strains Ya-60, B-60, Z-61, and C-61 were analyzed with respect to their antigenic specificity by HIT and were found to be antigenically distinct from the human H1 and H2 viruses. 47 After the appearance of the H3 pandemic virus in 1968, some of the Ukrainian duck strains were shown to be antigenically 48, 49 Moreover, HIT testing also showed that the B-60 and BV1 strains of the virus reacted with human sera, including those collected in 1881À1886 and in 1905À1908. On the basis of this phenomenon, the authors suggested that an avian virus similar to the strains B-60 and BV1 was the precursor of the human pandemic strain and that this antigenic variant had appeared in humans several times in the past. 48 Formerly known as Ya-60, strain A/ duck/Ukraine/1/1960 was shown 50 to belong to the H11N2 subtype, whereas A/duck/ Ukraine/2/1960 was identified as H3N6 and A/duck/Ukraine/1/1963 as H3N8.

The highly pathogenic H5N2 and H7N2 strains were isolated from chickens in the Moscow region. 51, 52 Several virus strains producing enteritis in chickens were isolated in 1972 and in 1974 in chicken farms and identified as H6N2 strains, 51,53,54 an unusual antigenic formula for a pathogenic virus affecting poultry. Six H3N2 isolates were obtained in a chicken farm in Kamchatka from chickens affected with rhinitis, conjunctivitis, and laryngotracheitis. 51, 55 In 1977, isolates identified as H3N1 viruses were isolated from sick chickens and ducks in the Russian Federation 25 and Uzbekistan in the former USSR. 26 In 1984, H8N4 strains were isolated in the western part of the Ukrainian Soviet Republic from the lungs of ducklings affected with pneumonia. The isolation was the only one of an H8 influenza virus in the USSR (Lvov DK, unpublished data).

In 1970, a large-scale series of virus isolations from wild birds, combined with some serological studies, was initiated as a part of the Coordinated Program of the National Committee on the Studies of Viruses Ecologically Linked to Birds together with the Virus Ecology Center of the D.I. Ivanovsky Institute of Virology. By the end of the 1970s, the pattern of circulation of avian viruses in the territory of the USSR was identified. 3, 11, 26, 30 In the ensuing years, the pattern of the Influenza A virus subtypes (including H15 and H16) circulating in Northern Eurasia was amplified (Figure 8.92 ).

Blood sera collected in the spring and autumn of 1970 near Lake Khanka and Peter the Great Bay (both in Primorsky Krai) from 262 birds-mainly mallards (Anas platyrhynchos), common teals (An. crecca), Baikal teals (An. formosa), garganeys (An. querquedula), falcated ducks (An. falcata), pintails (An. acuta), grey herons (Ardea cinerea), coots (Fulica atra), black guillemots (Cepphus grylle) and blacktailed gulls (Larus crassirostris)-were HITtested against H1, H4, H5, H6, H10, and H11 avian influenza viruses. No antibodies were found in the sera of grey herons and coots, nor were any found against H11 in any species. Antibodies against all the other subtypes tested were encountered occasionally in the sera of gulls, black guillemots, and ducks. In some species, such as teals, falcated ducks, and black guillemots, antibodies against several subtypes were detected. 27 In 1972, sera were collected from gulls, cormorants, murres, and tufted puffins in the Commander Islands. Antibodies against H2, H3, H5, and H7 viruses were detected. 28 In 1970À1972, sera from gulls, cormorants, and murres were collected in the Kamchatka, Sakhalin, and Magadan regions and antibodies to H1, H2, H3, H5, H6, and H7 viruses were detected. 30 Antibodies against H1, H3, H4, H5, and H7 were identified in sera taken from Arctic terns (Sterna paradisaea), black-throated loons (Gavia arctica), mallards (Anas platyrhynchos), common teals (Anas crecca), tufted ducks (Aythya fuligula), greylag geese (Anser anser), skuas (Stercorarius sp.), and a blue whistling thrush (Myophonus caeruleus) collected in the White Sea Basin in the estuary of the Pechora River in the Arkhangelsk region of Russia in 1969À1972. 56 The serologic studies suggested a wide range of avian influenza viruses circulating in wild birds in Northern Eurasia. This suggestion was confirmed and extended by the isolation of virus strains from other wild birds.

Many avian species proved to be hosts of H1 viruses. A virus belonging to the H1N3 subtype was isolated in 1977 from a tern in the southern part of the Caspian Sea basin. 57 In 1978, an H1N4 strain was isolated from a common teal (Anas crecca) in the Russian Republic of Buryatia in eastern Siberia. 41 Several H1N1 viruses were isolated in Kazakhstan in 1979 from waterfowl, including the common teal (An. crecca), garganey (An. querquedula), shoveler (Spatula clypeata), and coot (Fulica atra), 58 as well as in 1980 from tree sparrows (Passer montanus) and hooded crows (Corvus cornix). 41 In 1979, an H1N1 virus was isolated from a hawfinch (C. coccothraustes) in Mongolia. 59 In the same year, an H1N2 strain was isolated from a black-headed gull (Larus ridibundus) on an island in the northern part of the Caspian Sea. 41 The avian viruses belonging to the H2 subtype seem not to be abundant in Russia. In fact, for a long time the only virological evidence of the presence of this subtype in Russia was the isolation of an H2N3 virus in 1976 from a pintail (Anas acuta) in Primorsky Krai. 60 However, serological data suggested that H2 viruses circulated in wild birds not only in Primorsky Krai, but also in other regions of the Far East, including the Commander Islands as well as the Kamchatka, Sakhalin, and Magadan regions. 54, 61 Avian influenza A viruses belonging to the H3 subtype are widespread in Northern Eurasia. An H3N2 virus was isolated from a common murre (Uria aalge) in 1974 on Sakhalin Island, 62 and another H3N2 strain was isolated in 1976 from a pintail (Anas acuta) in Primorsky Krai. 63 Two H3N2 strains were isolated in 1974 in the Ukrainian Soviet Republic from unusual hosts for avian viruses: the white wagtail (Motacilla alba) and the European turtle dove (Streptopelia turtur). 64 H3N2 strains were also isolated from grey crows (Corvus cornix) in 1972 in the Volga basin and from a shelducks (Tadorna ferruginea) in 1979 in Kazakhstan. 65 An H3N2 virus was isolated from a tree sparrow (P. montanus) in 1983 in the Ukrainian Soviet Republic. 66 In 1972À1973, H3N3 and H3N8 viruses were isolated from ducks and herons in Khabarovsk Krai. One of the viruses closely resembled a strain isolated a year later in central Asia. This resemblance demonstrated that H3N3 viruses circulated in regions fairly distant from one another. 67 In 1972À1973, H3N8 viruses were isolated in Khabarovsk Krai from wild ducks (Anas sp.), tufted puffins (Fratercula cirrhata), and horned puffins (F. corniculata) 65 and in the Arkhangelsk region in the Pechora River estuary (White Sea basin) from Arctic terns (Sterna paradisaea) and black-throated loons (Gavia arctica). 68 In 1978, H3N8 strains were isolated in the Republic of Buryatia from a mallard (An. platyrhynchos) and a pintail (An. acuta), 65 as well as in Khabarovsk Krai from the common murre (U. aalge) 67 and from black-headed gulls (Larus ridibundus). 69 Avian viruses of the H4 subtype were isolated in 1970À1980 mostly in a narrow belt stretching from the lower Volga, through Kazakhstan, and on to the south of eastern Siberia. Several H4N6 strains were isolated in 1976 from slender-billed gulls (Chroicocephalus genei) in the Volga delta 70 and from great black-headed gulls (Ichthyaetus ichthyaetus) on the islands in the northern part of Caspian Sea. 41 In 1977, H4N8 virus was isolated from the black tern (Chlidonias niger) in Central Kazakhstan. 71 In the Republic of Buryatia, H4N6 strains were isolated in 1978 from the common goldeneye (Bucephala clangula). 41 Isolations of H5 influenza viruses from wild birds were scarce. In 1976, several H5N3 strains were isolated from terns (common terns and little terns) and a slender-billed gull in the Volga River delta. 70 A detailed description of the penetration of the H5N1 strain of of highly pathogenic avian influenza (HPAI) A into Northern Eurasia and its further dissemination is presented shortly.

The strains belonging to the H6 subtype seem not to be abundant, but their geographic distribution is wide. An H6N2 strain was isolated in 1972 from the Arctic tern (Sterna paradisaea) 68 in the Arkhangelsk region (White Sea basin). One H6N4 strain was isolated in 1978 from the pintail (Anas acuta) in Primorsky Krai, 41 and an H6N8 strain was isolated from the common tern (S. hirundo) in 1977 in the Caspian Sea basin. 57 In 2010, two H6N2 strains were isolated on Kunashir Island (the southernmost of the Kuril Islands) and four were isolated on Sakhalin Island.

An H7N3 strain was isolated in 1972 from a sandpiper (a member of the Scolopacidae family) in the Arkhangelsk region of Russia. 68 One strain of H8N4 was isolated in 2001 in the Republic of Buryatia, and one strain in 2003 in Mongolia.

An H9N2 strain was isolated from a mallard (Anas platyrhynchos) 72 in Primorsky Krai in 1982 and in Khabarovsk Krai in 2013.

Over 40 H10N5 strains were isolated from a wide array of bird species near Alakol Lake in east central Kazakhstan in 1979. The strains were isolated from several species of ducks (Anas sp.), from shorebirds (members of the order Charadriiformes), to passerine birds (members of the order Passeriformes), to coots (Fulica atra), plovers (members of the family Charadriidae, subfamily Charadriinae), and chukars (Alectoris chukar). 41 This situation is a rare case of an isolation of closely related viruses from an extremely wide array of avian species.

The viruses identified as H11N8 strains were isolated in 1972 from the Arctic tern (Sterna paradisaea) and the red-throated diver (Gavia stellata) in the estuary of the Pechora River in the northern part of European Russia. 54 Several H11N6 strains were isolated from the common teal (Anas crecca), the European widgeon (An. penelope), and the European golden plover (Pluvialis apricaria) in 1979 in eastern Siberia. 41 In 1987, H12N2 strains were isolated from mallards, a pintail, and European widgeons south of Issyk-Kul Lake in Kyrgyzstan. 72 Two strains of H12N2 were isolated from wild ducks (subfamily Anatinae) in Kyrgyzstan.

The results of virus isolation and serological studies in the territory of the USSR in 1970À1980 suggested a wide circulation of avian influenza viruses in wild birds and enabled researchers to construct a map of avian influenza viruses encountered in different regions of Northern Eurasia. The general pattern of distribution of influenza virus subtypes in wild birds was fairly evident by the end of the decade. Virus isolation was continued in the ensuing years, and it brought 290 8. SINGLE-STRANDED RNA VIRUSES several major results. Isolations were performed mostly in the central and southern parts of European Russia, in western and eastern Siberia, and in the Russian Far East. 72 Overall, 1,005 strains were isolated from wild birds in Russia in 1980À2013 (Table 8 .49). About 250 samples were taken yearly from 50 to 100 birds in each geographic region. The mean percentage of successful isolations ranged from 3.5% to 5.7%. Over 50% of the isolates were H13 viruses (H13N2, H13N3, H13N6, and H13N8) isolated mostly from gulls and shorebirds in the northern part of the Caspian Sea. The viruses of the H3 subtype (over 25% of the total number of isolates) were isolated in several regions.

Many strains isolated in 1979À1985 from great black-headed gulls (Ichthyaetus ichthyaetus), herring gulls (Larus argentatus) and Caspian terns (Hydroprogne caspia) on the island of Maly Zhemchuzhny in the northern part of the Caspian Sea were not identified at the time of isolation with respect to the subtype of their HA. As it turned out, the strains belonged to the subtype H13, was first described in 1982, 73 and in 1989 the mysterious Caspian isolates were identified 74 as H13N2, H13N3, and H13N6. To characterize the H13 subtype molecularly and antigenically, the complete nucleotide sequence of the HA of the strain A/great black-headed gull/Astrakhan/ 277/84 was used for comparison with the HAs of two American strains isolated from a gull and a pilot whale. 75 Virus isolation studies in the northern Caspian basin were continued in the 1990s and 2000s. Materials were collected from wild birds in the area of the northern coast of the Caspian Sea (including Maly Zhemchuzhny Island) from the delta of the Terek River in the north Caucasus region to the Emba River in western Kazakhstan. Most of the strains that were isolated belonged to the H13 subtype, including H13N2, H13N3, H13N6, and H13N8 isolates; besides these strains, only single isolates belonging to the H4N3, H4N6, H6N2, and H9N2 subtypes were isolated. 76, 77 In 1990, a new, previously unrecognized, subtype of influenza virus H14 HA was described 78 on the basis of the characterization of two strains isolated in 1982 from mallards (Anas platyrhynchos) in the Ural River delta. The H14N5 and H14N6 subtypes were isolated from mallards and gulls in Astrakhan. 76 A partial sequencing revealed that NS gene of the H14 strains isolated from the gulls was closely related to the NS gene of H9 and H13 strains isolated previously from gulls and terns in the Caspian Sea basin and to the H9N4 strain isolated in the Russian Far East. The NS gene of an H14N5 strain isolated from a mallard was much more distantly related to the NS gene of the viruses isolated from gulls. 76 The results suggest that reassortment events play a significant role in the evolution of H14 viruses, with the NS gene being an important determinant of the range of the host.

A large-scale isolation of avian influenza viruses from fecal samples was performed in 1995À1998 in eastern Siberia and the Far East by a group that included both Russian and Japanese researchers. 79 Scientific contacts between Russian and Japanese researchers of avian Influenza A virus were ongoing during the eighth RussianÀJapanese Consultations at a conference titled "Protection of Migratory Wild Birds in the AsiaÀPacific region" held at the Russian Ministry of Natural Resources in Moscow April 01À05, 2011. At the conference, the D.I. Ivanovsky Institute of Virology took the initiative to renew the international meetings on medical ornithology at the level of experts of AsiaÀPacific countries that had been taking place regularly during the 1970 and 1980s. As a result, the First International Meeting for Medical Ornithology in the AsiaÀPacific Region was held in Tokyo, Japan, on June 23, 2011. The meeting was devoted to the topic of HPAI H5N1 distribution in Asia. A second meeting was conducted in Moscow at the D.I. Ivanovsky Institute of Virology March 15À16, 2012 (Figure 8.93) . 80 In the summer of 2000 in a valley in the Sayan Mountains in southeastern Siberia, the strains H3N8, H7N1, H7N8, H13N1, and H13N6 were isolated. 81 The H3N8 and H7N8 strains were isolated from ruddy shelducks (Tadorna ferruginea) and common redshanks (Tringa totanus), the H7N1 strains from common pochards (Aythya ferina), and the H13N1 strains from northern shovelers (Anas clypeata) and great crested grebes (Podiceps cristatus). The H13N6 strains were isolated from all of the aforementioned species, as well as from teals, ducks, and terns. In 2000À2002, the subtypes H3N8, H4N2, H4N6, H4N8, H4N9, H5N2, H5N3, H9N2, and H13N6 were isolated in the same region; 1,750 samples were taken from 48 bird species. 72 A strain isolated from the muskrat (Ondatra zibethicus) 81 in 2000 in the Republic of Buryatia was identified as an H4N6 virus closely resembling the H4N6 strains isolated from ducks in the same year and the same region. 72 The HAs of the H4 strains (including the muskrat strain) isolated in Buryatia formed a separate group of the EurasianÀAustralian branch in the phylogenetic tree of H4 HA (Figure 8.94 ). They had a C-terminal proline residue in their HA1 subunit, in contrast to the serine residue of most Eurasian strains. The HA genes of the H5N2 isolates turned out 82 to have cleavage peptides LRNVPQRETR/GL identical to the ones of the low-pathogenic strains isolated from ducks in Hong Kong and Malaysia. In contrast, the HAs of H3 and H4 strains isolated from teals in 2002 and from mallards in 2003 near Lake Chany in Novosibirsk Region western Siberia, were related to the HAs of the European H3 and H4 strains. 83, 84 Interestingly, the HAs of the H3 strains were closely related to the HA of A/duck/Ukraine/1/1963 (H3N8). 83 However, unlike the Has of H3 and H4, the HAs of H2 strains isolated in the same area in 2003 from mallards resembled the HAs of H2 strains isolated in 2001 in Japan from mallards (Anas platyrhynchos). 84 In 2003, influenza A virus strains belonging to a rare subtype H8N6 were isolated in Mongolia from the great cormorant (Phalacrocorax carbo), white wagtail (Motacilla alba), and magpie (Pica pica). 85 Penetration of HPAI H5N1 into Northern Eurasia: Reasons and Consequences. During longitudinal wide-scale monitoring of Influenza A viruses among wild bird populations in Northern Eurasia, several H5N2 and H5N3 strains were isolated in 1976 and 1981 in the Caspian Sea basin. 70, 74 More recently, in 1991À2001, strains belonging to the same subtypes were isolated in Siberia, and their features proved to be relevant to H5 virus circulation. Onn the one hand, the HAs of the strains isolated from teals in 2001 in Primorsky Krai, as well as the HAs of strains isolated from a mallard in Lake Chany in western Siberia in 2003, were shown to be closely related to HAs of H5 strains isolated in 1997 in Italy from poultry. 79, 82 On the other hand, the HA of the H5N3 strain isolated from a wild duck as early as 1991 in Altai Krai in southwest Siberia was closely related to the HA of A/duck/Malaysia/F119-3/ 1997 (Figure 8 .95). The HA of the Altai (1991) and Lake Chany (2003) viruses had a monobasic HA1ÀHA2 cleavage site, and, accordingly, it had a low-pathogenic avian influenza (LPAI) phenotype. 72, 79, 82, 86 Besides the amino acid sequence of the HA, the sequences of other genes of the H5 viruses isolated in Russia proved to be relevant. The NP genes of the H5N2 and H5N3 strains isolated in Primorsky Krai in 2001 formed a separate cluster in the phylogenetic tree, together with the NP genes of the H4N6 strains isolated from common shelducks (Tadorna ferruginea) and common pochards (Aythya ferina) in the Republic of Buryatia in 2000, the H2N3 strain isolated from the northern pintail (Anas acuta) in Primorsky Krai in 1976, and the 43, 72 However, they were very distantly related to the NP genes of H3N8, H6N1, and H5N1 strains isolated from poultry and humans in southeast Asia in 1996À2001 and to the NP genes of H4N8 viruses isolated from wild ducks in the Caspian Sea basin in the European Russia in 2002. By contrast, unlike the NP genes, NS genes of the strains from Primorsky Krai were closely related to the NS genes of the H5N1 and H4N8 viruses isolated in southeastern Asia in 1997À2001, as well as to the NS genes of an H4N8 virus isolated in the Caspian Sea basin in 2002 (Figure 8.97) . 43, 72 An abundance of influenza A subtypes in the avian populations of Northern Eurasia provides excellent conditions for gene exchange. The extent of the exchange is demonstrated by the relatedness of different genes of the Russian isolates to the genes of European strains, on the one hand, and South Asia isolates, on the other. 72, 76, 83, 84 The exchange is to a certain extent restricted by host specificity, but this restriction is not rigid, and the virus genes frequently traverse interspecies barriers. Avian migration routes crossing Russian territory are an important factor in the gene flow. The extensive intra-and interspecies contacts in the natural habitats of wild birds in Russia stimulate rapid virus evolution and the appearance of new variants through reassortment events and, presumably, through the postreassortment adjustment of genes, thereby restoring the functional intergenic match. 87, 88 Another factor may be the occurrence of avian influenza viruses in lake water, first registered in 1979 in eastern Siberia. 41 This phenomenon might provide a means for the temporal as well as territorial transfer of genes, as suggested by the recent detection of influenza 89 Thus, the sequencing data suggest that there exists an extensive exchange of genes of the avian influenza viruses circulating in Europe, Siberia, and southeast Asia along the avian migration routes connecting Europe, through the Russian territory, with southeastern Asia, the cradle of potentially pandemic reassortant viruses. After the highly pathogenic H5N1 viruses began disseminating from southeastern 82 Our second prediction was that overwintering migrating birds could transmit the HPAI virus into Northern Eurasia during their spring migration. We discussed two possible routes by which the birds might introduce the virus: the Dzungarian (IndianÀAsian) migration route and the AsianÀPacific route. Preparing for these two possibilities, we increased our surveillance in the southern part of western Siberia (through the Russian Foundation for Basic Research Project 03-а04-49158) and in Primorski Krai (through the International ScienceÀTechnical Center Project 2800) in the spring of 2004. In April of 2005, a wide epizootic outbreak emerged at Kukunor Lake (also called Qinghai Lake) in Qinghai Province, China, and from this location the virus could spread through the Dzungarian Gate, which links the northwestern mountain ranges of Tibet with the western Siberian lowland. Our second prediction was confirmed as well, when HPAI H5N1 first appeared in Northern Eurasia, in western Siberia (Novosibirsk Region, Russia) in the summer of 2005 (Figure 8.98 ). Although the official start of the epizootic among poultry was dated July 10, 2005 (Table 8 .50), that one occurred among wild birds about 2 weeks before was retrospectively established. 5 The outbreak spread quickly and caused over 90% lethality among poultry.

The virus isolations in the area were performed independently by two groups of researchers. A number of strains were isolated in Zdvinsky District, Novosibirsk Region, by a group of researchers from the D.I. Ivanovsky Institute of Virology in Moscow. The materials for isolation (cloacal and tracheal swabs, pools of internal organs, and blood) were taken from dead, sick, and healthy birds at the farm where the epizootic occurred and from wild birds in the vicinity. 90, 91 Three strains were isolated from dead chickens (Gallus gallus domesticus), two strains from sick or dead ducks (Anas platyrhynchos domesticus), and one strain from a healthy great crested grebe (Podiceps cristatus). All of the strains were deposited into the Russian State Collection of Viruses functioning under the auspices of the D.I. Ivanovsky Institute of Virology ( 93 Several features of the primary structure of virus proteins, such as Lys627 residue in PB2 and Glu92 residue in NS1, characteristic of highly virulent variants of H5N1 viruses, correlated with the high pathogenicity of the Novosibirsk isolates. A deletion in the NA gene in amino acid positions 49À60 indicated that the strains belonged to the genotype Z, which dominated in 2004 in southeastern Asia. 94 The other group of strains was isolated by a team of researchers from the State Research Center of Virology and Biotechnology VECTOR (also known as the Vector Institute) in Koltsovo, Novosibirsk Region. Two strains were isolated from chickens and one strain from a turkey in the village of Suzdalka, Dovolnoe District, in July 2005. The viruses were isolated from homogenates Guangdong Province, China. 95 The viruses were highly pathogenic to chickens in a laboratory test. 96 Our third prediction was that the virus would move with the migrating birds to their overwintering locations. As it turned out, coincident with this prediction, epizootic outbreaks occurred along the main migration routse in the Urals, the Russian Plain, Europe, Africa, central Asia, and India Figure 8 .99), 102 indicating the distribution of the virus through the eastern European flyway of birds (Figure 8 .100), connecting western Siberia, the Russian Plain, eastern Europe, the Middle East, and Africa. 54 Our fourth prediction was that the virus would return in birds migrating from their overwintering places to Northern Eurasia in the spring of 2006, with a widening of the epizootic. Dramatic events occurred June 10À28, 2006, at Uvs-Nuur Lake, which is situated on the boundary between the Great Lakes Depression of Mongolia and the Tyva Republic of Russia (Figure 8.98 ). An estimated 3,000-plus birds died in the Russian part of this lake, which is only about 1% of the total area of the lake. The species most affected was the great crested grebe (Podiceps cristatus); as also affected were coots (Fulica atra) and cormorants (Phalacrocorax carbo). Terns and gulls were involved in the epizootic to a significantly less extent. The absence of poultry farms in the vicinity of Uvs-Nuur Lake precluded outbreaks among poultry. The Tyva strains appeared to be the beginning of a new genetic lineage in the QinghaiÀSiberian genotype 2.2. The lineage was designated as a TyvaÀSiberian subgroup 104 (Figure 8 .99) that was isolated not only in Siberia, but also in Europe. It is believed (Table 8 .51) from dead and sick poultry, and all the isolates were identified as HPAI H5N1 (Table 8 .52) with a high level of sequence similarity to the QinghaiÀSuberian genotype 2.2 (Figure 8.99) . This outcome implied a common source of infection for all the local outbreaks ( Figure 8.101) , and subsequent epidemiologic investigation demonstrated a link to live-bird markets in Moscow, where the affected farmers had purchased poultry several days before.

A complete genome analysis of the prototype A/ chicken/Moscow/2/2007 revealed 105 Group of strains is shown with the use of braces: Designations common to all strains in the given group are shown outside the braces; the variable part of the designations is cited inside the braces; the asterisk "*" means "any designation." Only mutations that are found in all the strains of the given group are listed in the table.

b Bold font indicates substitutions with respect to HPAI/H5N1/2.2 consensus; the frame -substitutions unique to Northern Eurasian strains (Tables 1À2)-that is, they did not occur among Northern Eurasian strains previously; the frame with grey background -substitutions unique to all HPAI/H5N1/2.2 genotypes (strains isolated in both Northern Eurasia and other places); {kc-substitution that takes place in the strains of the given epizootic outbreak only; {£c-substitution that takes place in the strains of both the given and later or previous epizootic outbreaks.

valley ecosystem in the north or south Caucasus in the winter of 2007 and was introduced into the live-bird market through contaminated poultry cages or contaminated grain.

In September 2007 , an outbreak was detected in the northeastern part of the basin of the Sea of Azov on a chicken farm called "Lebyazhje-Chepiginskaya" in the Krasnodar region of Russia (Figure 8.98) . The virus isolates-A/ chicken/Krasnodar/300/2007 from poultry and A/Cygnus cygnus/Krasnodar/329/2007 from a sick whooper swan (Cygnus cygnus) found in a "liman" (shallow gulf) near the farm-were closely related to each other (they had two synonymous nucleotide substitutions in PB1, two synonymous in PB2, one nonsynonymous in M1, two nonsynonymous in NA, and one nonsynonymous in NS1) and belonged to the IranÀNorth Caucasian subgroup of QinghaiÀSiberian genotype 2.2 (Figure 8 .99). The isolated strains contained 10 unique amino acid substitutions with respect to a QinghaiÀSiberian consensus in PB2, PA, HA, NA, and NS1, suggesting that regional variants were continuing to emerge. 106 In December 2007, a poultry farm called "Gulyai-Borisovskaya" in the Rostov region became infected (Figure 8.98) . Unfortunately, the infection was not reported in time, and infected poultry manure was spread on adjacent fields, where wild terrestrial birds could be infected. 107 This exposure is thought to have contributed to the infection of a number of species. including rooks (Corvus frugilegus), jackdaws (Corvus monedula), rock doves (Columba livia), common starlings (Sturnus vulgaris), tree sparrows (Passer montanus), house sparrows (Passer domesticus), and more. Surveillance of these species by RT-PCR detected H5 virus in 60% of pigeons and crows, in around 20% of starlings, and in 10% of tree sparrows, all without clinical features. These results were confirmed by viruses isolated from wild birds and poultry (Table 8 .51). Birds whose infection was confirmed by RT-PCR and virus isolation seemed reluctant to move and had ruffled feathers. On necropsy, the birds were observed to have had conjunctivitis; hemorrhages on the lower extremities and in muscle, adipose, intestine, mesentery, and brain tissue; and changes in the structure of the pancreas and liver. Wide involvement of wild terrestrial birds in virus circulation, presumably from the exposure to infected chicken manure, distinguished this outbreak from others. Genome analysis ( The QinghaiÀSiberian clade includes viruses that have infected and caused severe disease and mortality in humans, but currently they do not appear to be transmitted efficiently in humans. Upon analyzing representative viruses in our collection for their potential to replicate in mammals, we found that isolated strains replicated effectively in mammalian cell culture lines BHK-21, LECH, Vero E6, MDCK, and SPEV. 5, 108, 111 PB2 has consensus K627 that promotes virulence in mammalian cells. 93 On the basis of the amino acid sequence of HA receptor-binding sites of QinghaiÀSiberian isolates containing E202, Q238, and G240, its affinity of Qinghai Siberian isolates for α2 0 -0 À3 0sialic acids was predicted. However, a double mutation Q- 238 L and G-240 S or just a single mutation E-202 D could switch HA receptor-binding affinity from avian to human receptors. 113 All the QinghaiÀSiberian isolates are sensitive to amantadine, rimantadine, and oseltamivir, as has been confirmed by both direct biological experiments in vitro 114 54 The first overwintering area could be the source for the IranÀNorth Caucasian subgroup, the second for the TyvaÀSiberian subgroup. Returning to their nesting areas in Northern Eurasia in the spring of 2006, wild birds afforded a mixed virus population the opportunity to spread (Figure 8.100) . 5, 24, 28, 42, 43, 108 A decrease in the potential of isolated strains to reproduce in vitro (Figure 8 .102) is more evident in poultry (TCID 50 5 11.847À0.272 3 t) than in to wild birds (TCID 50 Although HPAI H5N1 has penetrated into Northern Eurasia through the Dzungarian flyway of wild birds, this fact did not exclude the possibility of the virus transferring through other flyways -(e.g., through the Far EastÀPacific flyway). 54 Indeed, in April with wild waterfowl. One initial theory of the introduction of the virus to poultry was from the birds' exposure to hunted ducks, but the direct interaction of wild birds with poultry seems more likely. The isolates (see Table 8 .51) from dead chickens and the common teal (Anas crecca) collected in the vicinity of epizootic farms were identical and indicated a direct role of migrating birds in the introduction of the virus. The teal, which appeared to be the most likely source of infection of poultry, had no obvious behavior changes but did have hemorrhagic lesions in the intestines on necropsy. It is interesting to underline the fact that common teals were the source of isolation of H5 (Figure 8.99) . 117, 118 Fortunately, both clades (2.2 and 2.3.2.1) of HPAI H5N1 that had penetrated into Northern Eurasia had low epidemic potential because their receptor specificity did not switch from α2 0 À3 0 -to α2 0 À6 0 -sialoside affinity, a fact that was revealed by the primary structure of the HA receptor-binding region and direct testing in sialoside-based experiments in vitro. 5, 80 Thus, we discuss the epizootic event provoked by HPAI H5N1 in Northern Eurasia during 2005À2010 as a model of an emer-gingÀreemerging situation in need of permanent ecologo-virological monitoring.

Influenza A Viruses Among Mammals. The circulation of Influenza A viruses among swine (order Artiodactyla: family Suidae, genus Sus) was originally established in 1930 by Richard Shope (Figure 8 .84): His investigations not only established the viral etiology of swine flu and isolated the first historical strain A/swine/Iowa/15/1930 (H1N1), but also serologically demonstrated the close relation between human infection agents and those of swine. 11 Shope's findings gave rise to a number of isolations of swine respiratory disease agents. Many of these agents later turned out not to be Influenza A virus; for example, "Kö be porcine influenza virus," isolated in Germany; 119 "infectious pneumonia of pigs;" 120,121 "BeveridgeÀBetts virus" 122 (more often, these pathogens belonged to Chlamydia sp.); and "Hemagglutinating virus of Japan," 123,124 which initially was named "Influenza D virus" and was later identified as Sendai virus (SeV) (family Paramyxoviridae, genus Respirovirus). 125 Nevertheless, a number of strains isolated at the end of 1940s in Korea (strain Oti), 126 and in the 1950s and 1960s in Lithuania (prototype A/swine/Kaunas/353/ 1959), 127 Estonia, 128 Poland, 129 and Russia 130 were identified as Influenza A (H1N1) virus. Also, in the middle of twentieth century, Influenza A strains closely related to A/ swine/Iowa/15/1930 (H1N1) were isolated in Czechoslovakia 131,132 and Hungary. 133 Finally, after the beginning of the "Asian flu" pandemic in 1957, swine Influenza A (H2N2) virus strains were isolated initially in China 134 and later in Czechoslovakia 135 The principal peculiarity of pigs is the presence of both α2 0 À6 0 -sialosides (typical of human cells) and α2 0 À3 0 -sialosides (typical of avian cells) on the surface of respiratory tract cells. This feature permits both human (or adapted swine) and bird Influenza A virus strains to circulate simultaneously, giving rise to conditions favorable to the reassortment and emergence of virus variants with suddenly appearing new properties. 42,136À143 Avian Influenza A virus strains have been demonstrated to initiate productive infection in swine under experimental conditions. 31,144À147 The great number of reassortment forms of Influenza A viruses isolated from swine constitute evidence of the extremely high reassortment potential of the swine viral population. Thus, A/swine/England/191973/1992, isolated from nasal swabs of sick pigs in Great Britain in 1992, belongs to the unique H1N7 subtype, which was formed by the reassortment of A/USSR/90/1977 (H1N1) (the source of PB2, PB1, PA, HA, NP, and NS segments) and A/equine/Prague/1/1956 (H7N7) (the source of NA and M segments). 148 151 The most evident illustration of the reassortment potential of swine populations is the emergence of the pandemic "swine flu" H1N1 pdm09 in 2009 as the result of the reassortment of two swine genotypes of the H1N1 subtype: the "American swine genotype" (the source of PB2, PB1, PA, HA, NP, and NS segments) and the "European swine genotype" (the source of NA and M segments) (Figure 8.104 ). 24À29 Using different receptor-mimicking sialosides (Table 8 .55), we investigated the evolution of receptor specificity in Influenza A (H1N1) pdm09 virus during pandemic and postpandemic epidemiological seasons. Different types of sialoside specificity spectra are presented in Figure 8 .105.

To compare α2 0 À3 0 -and α2 0 À6 0 -sialoside specificities, we introduced the special parameter W 3/6 , which is the ratio of the optical density for flat α2 0 À3 0 -sialosides (3 0 SL and 3 0 SLN) to the optical density for flat α2 0 À6 0 -sialosides (6 0 SL and 6 0 SLN):

If W 3/6 is ,1 (W 3/ 6 , 1.00), then α2 0 À6 0 -specificity dominates. In contrast, if W 3/6 . 1.00, then α2 0 À3 0 -specificity dominates. (Strains with W 3/6 % 1.00 have approximately equal α2 0 À3 0 -and α2 0 À6 0specificities.) 152 The sialoside specificity of the first pandemic strains isolated in our study, A/California/04/2009 (H1N1) pdm09, demonstrates dual affinity to both α2 0 À3 0 -and α2 0 -6 0 -sialosides (Figure 8.106) . Therefore, such strains might be able to effect swineÀhuman and humanÀhuman transmission, and their pathogenicity is higher than that of seasonal influenza viruses (W 3/6 % 1 Pigs could be the source of Influenza A virus not only in humans, but also in synantropic animals. S. Agapov published an article on the pathogenic properties of Influenza A virus specimens isolated from brown rats (Rattus norvegicus) in pigsties. 161 Experimental infection of swine influenza A virus strains in rodentsmice (subfamily Murinae) and hamsters (subfamily Cricetinae)-has been described in a number of publications. 3,133,146,161À163 Rodents have become a widely used laboratory model for Influenza A virus. Productive infection in laboratory mice (order Rodentia: family Muridae, genus Mus) was revealed in a pioneer publication 13 of W. Smith (Figure 8 .85), C. Andrewes (Figure 8 .86) and P. Laidlaw (Figure 8.87 ). Adapted to mice, Influenza A virus strains are widely used to investigate infectious process, pathology, and the efficiency of antivirals. 161,164À168 In 2000, the strain Influenza A/muskrat/ Buryatia/1944/2000 (H4N6) was isolated from muskrat (Ondatra zibethicus) hunted in the Selenga River delta, near where it empties into Lake Baikal. Despite mountain relief along the lake coast, the delta represents a sandbank wedge overgrown with low reeds where the conditions are conducive to a mass nesting of ducks and a high density of population of muskrats. As a result, there is a high level of interaction between the populations of aquatic birds and muskrats. In particular, A/muskrat/Buryatia/ 1944/2000 (H4N6) has the highest homology with A/pochard/Buryatia/1903/2000 (H4N6). The strain from muskrat turned out to be virulent to mice without any preliminary adaptation, like the majority of H4 strains from Siberian ducks. It was suggested that virulence was promoted by an R220G mutation in HA. 72, 81 The Russian State Collection of Viruses contains the Influenza A/Sciurus vulgaris/ 

6Su-6 0 SLN 6-Su-6 0 -sialyllactose: 6-Su-Neu5Acα2-6Galβ1-4Glcβ

Primorje/1004/1979 strain with an undetermined subtype isolated from a red squirrel (Sciurus vulgaris). 5 Weasels (order Carnivora: family Mustelidae) are another sensitive group of hosts for Influenza A viruses. The sensitivity of the domestic ferret (Mustela putorius furo), an albino form of the forest polecat (Mustela putorius), to the virus was explored even in the earliest scientific publications devoted to Influenza A virus. 13, 14 Today, ferrets are the best animal model of Influenza A virus infection. In particular, sera of infected ferrets (as well as infected rats) are widely utilized for Influenza A virus subtype identification.

In 1985, Japanese scientists demonstrated that the epidemic strain A/Kumamoto/ 22/1977 (H3N2) was able to provoke disease in the European mink (Mustela lutreola), 169 and perhaps it was this virus that caused a respiratory disease epizootic on Japanese fur farms during 1977À1978. In 1984À1985, during an epizootic among minks in Sweden, six strains of Influenza A (H10N4) virus (prototype A/ mink/Sweden/E12665/1984) were isolated and turned out to have an avian origin. 170 In 2007, an Influenza A/stone marten/Germany/R747/06 (H5N1) strain was isolated from the internals of a stone marten (Martes foina) that was found dead in a place where there was mass mortality of birds in Germany. 171, 172 The circulation of Influenza A virus among cats (order Carnivora: family Felidae) was originally established in 1942 by the Japanese virologists J. Nakamura and T. Iwasa: Strain A/cat/Fusan/1/1942 (known as "Chiba virus") 173 turned out to be an avian strain of the H7N7 subtype. 168 In 1970, C.K. Paniker and C.M. Nair described the successful experimental infection of adult cats and eight-monthold kittens by A/Hong Kong/1/1968 (H3N2), of the "Hong Kong flu" pandemic strain. 174 A number of H5N1 strains from Felidae members-tigers (Panthera tigris), 175À177 leopards (P. pardus), 176 and domestic cats (Felis catus) 178À180 -were described after 2005.

The first experiment involving the infection of dogs (order Carnivora: family 178 this strain had an avian origin, but provoked lethal pneumonia in dogs. 186 It is noteworthy that Influenza A virus can be isolated from nasal swabs of dogs during inapparent infection, 187 so this virus might be more widely distributed among dogs than is usually considered. Influenza A virus is often the cause of pericarditis in dogs. 188 The circulation of Influenza A viruses among horses (order Perissodactyla: family Equidae, genus Equus) was originally explored in 1956 by a group of Czechoslovakian scientists headed by Bella Tumova (Figure 8 .107). In that year, a widespread epizootic emerged among horses (Equus ferus caballus) and the historical strain A/equine/Prague/1/1956 was isolated. 189 A subtype of this strain was given an initial designation H eq1 N eq1 and later was identified as H7N7 (but, for a long time, veterinarians designated this subtype as equine influenza type 1). 146 Later, Influenza A (H7N7) strains were isolated in other European countries 190 and the United States. 191 During the "Asiatic flu" pandemic of 1958À1961, a number of strains of Influenza A (H2N2) were isolated from sick horses in the Moscow region of the former USSR 192 

Hungary. 133, 163 It was shown that these strains were significantly different from A/equine/ Prague/1/1956 (H7N7), belonged to the H2N2 subtype, and had a human origin.

Equine Influenza A type 2 was originally found in 1963 in Miami, Florida, in the United States, when the prototypical strain A/equine/ Miami/1963 was isolated and designated as subtype H eq2 N eq2 . 193 Later, this subtype was identified as H3N8 and was multiply isolated 194À196 in both North and South America. In the former USSR, Influenza A (H3N8) virus strains were isolated from horses in the Ukrainian Soviet Republic during a widespread epizootic in 1970 in the vicinity of Kiev. 31 The Russian State Collection of Viruses contains the Influenza A/equine/Mongolia/3/ 1975 (H5N3) strain, which originates from birds and over came the interspecies barrier to penetrate into the equine population.

The circulation of Influenza A virus among camels (suborder Tylopoda: family Camelidae, genus Camelus) was originally established by D. K. Lvov 59 (Figure 2 .36) in 1980. In December 1979, an epizootic of "contagious cough" among Bactrian camels (Camelus bactrianus) emerged in Mongolia. Thirteen strains were isolated from nasal swabs; 59 145, 198 Tajikistan, 199 and the Ukrainian Soviet Republic in the former USSR. 31 The circulation of Influenza A viruses among cattle has been confirmed by multiple serological data. 31,200À204 The first isolation of Influenza A strain from sick sheep (Ovis aries) (order Artiodactyla: family Bovidae, subfamily Caprinae) was carried out in 1959 by a group of Hungarian scientists under the direction of G. Takatsy during an epizootic among farm animals. 133, 163 The Strain A/sheep/Hungary/B111/59 (H2N2) isolated by Takatsy was later utilized by J.L. McQueen and F.M. Davenport for experimental infection in lambs, but they observed no clinical symptoms. 205 The circulation of Influenza A viruses among deer (order Artiodactyla: family Cervidae) was originally established by T.V. Pysina and D.K. Lvov when they isolated the A/Rangifer tarandus/Chukotka/1254/77 (H6N2) strain from slowed reindeer (Rangifer tarandus) in the Chukotka Peninsula. 206 The Russian State Collection of Viruses in the D.I. Ivanovsky Institute of Virology contains the strains A/ deer/Primorje/1201/78 (H1N1), isolated from red deer (Cervus elaphus) in Primorsky Krai, and A/Rangifer tarandus/Yamal/865/90 (H13N1), isolated from reindeer (R. tarandus) on the coast of the Barents Sea. Specific antibodies towards Influenza A (H1N1) and A (H3N2) were detected in the sera of red deer (C. elaphus) and elks (Alces alces) in the north of Germany. 207, 208 S.Q. Li established the presence of about a 10% immune layer toward Influenza A (H1N1) and A (H3N2) among Cervidae in the northeastern provinces of China. 209 The strain Influenza A/whale/Pacific Ocean/19/1976 (H1N3) (or, alternatively, A/ whale/PO/19/1976) from a whale belonging to the Balaenopteridae family (order Cetacea, suborder Mysticeti) and bagged in the South Pacific Ocean was isolated by a group of Soviet virologists under the direction of D.K. Lvov 210 (Figure 2 .36) in 1976. This strain turned out to be reassortant between human and avian virus variants. 211 Two strains of Influenza A virus were isolated by a group of American virologists under the direction of R. Webster 212 (Figure 2 .20) from slowed long-finned pilot whales (Globicephala melaena) near Portland, Maine, in the United States in 1984: A/whale/Maine/1/84 (H13N9) (from periapical lymph nodes in the lungs) and A/whale/Maine/2B/84 (H13N2) (from the lungs). Further molecular genetic investigation, carried out by a RussianÀAmerican group of scientists, revealed that Influenza A variants in gulls (family Laridae) were the source of these strains. 75 A number of Influenza A virus strains were isolated on the coast of North America: H4N5, 213 H4N6, 214 and H7N7. 215, 216 Thus, one could expect to find Influenza A viruses among seals in Northern Eurasia as well.

Pathogenesis. Epithelial cells of mucous membranes are the main targets of Influenza A viruses. Degeneration, necrosis, and further apoptosis, followed by tearing away of the epithelial cell layer take place as a result of the infection. Nevertheless, the main element of Influenza A virusÀinduced pathogenesis is lesions on the system of vessels; the lesions emerge as the result of the toxic effect of the virus, an effect that includes the multiple formation of active oxygen forms. The latter provoke the generation of hydroperoxides, which interact with lipids and phospholipids of the cell wall to oxidize their peroxide, thereby hindering transport across the cell membrane. 217À219 A subsequent increase in the permeability of vessels, the fragility of their walls, and a violation of the body's microcirculation result in hemorrhagic manifestations, from nasal bleeding to hemorrhagic hypostasis of the lungs and hemorrhages in the substance of the brain. 219, 220 Frustration of the circulation, in turn, defeats the nervous system. The pathomorphological picture is characterized by the existence of lymphomonocytic infiltrates around small and average-size veins, hyperplasia of glial elements, and a focal demyelinization that testifies to the toxic and allergic nature of the pathological process in the CNS during influenza. 219, 221, 222 The most significant factors involved in cell tropism of the Influenza A virus are the receptor assembly on the surface of the potential target cell and the ability of cell proteases to cleave HA into two subunits (HA1and HA2) followed by fusion peptide rescue. 223À227 For example, for avian Influenza A virus variants, there is an obvious threshold in the virulence level: so-called LPAI and HPAI. HPAI strains strike vascular endothelial and perivascular parenchymal cells as well as the cardiovascular system, quickly reproduce high titers in practically all internal organs, and cause systemic disease leading to death of a bird 1À7 days after infection. LPAI strains, to the contrary, reproduce in low titers, have a narrow tropism toward mucous in the digestive and respiratory tracts (Figure 8 .108), and cause enteritis or rhinitis with low mortality. (However, bird diseases connected with LPAI also cause significant damage to agriculture and can break the interspecies barrier, resulting in diseases that are dangerous to people). Wild aquatic and semiaquatic birds, which are natural reservoirs of Influenza A viruses, can have inapparent disease during either LPAI or HPAI infection. 5,24,27,28,39,41À43,53,226,228À230 The ability of HA to be cleaved by proteases depends on the amino acid composition of the proteolytic cleavage site: LPAI strains contain only one or two positively charged basic amino acids (K or R), whereas HPAI strains have an enriched amount of basic amino acids. 5,24,27,28,39,41,228À230 Nevertheless, pandemic strains with extremely high virulence in humans have only single basic amino acids within the limits of the proteolytic cleavage site (Table 8 .58). Still, it is noteworthy that LPAI could provoke human disease as well. Except for the amino acid composition of the proteolytic cleavage site of HA, the efficiency of the cleavage process depends on glycosylation of HA in the vicinity of this site. 231, 232 Amino acid substitutions that switch virus tropisms from avian to mammalian cells in different Influenza A virus proteins have been described: E627K, 112 144, 146, 219, 221 The classic diagnostic approach is to isolate the virus with the use of sensitive biological models (ferrets, developing chicken embryoa, and cell lines). Influenza A virus infection could be retrospectively detected by HIT 239 or neutralization testing, but the most effective diagnostic methods are RT-PCR and biological microchips.

Control and Prophylaxis. Vaccination, together with the forced slaughter of livestock. is the most effective and accessible approach to Influenza A prophylaxis among domestic animals. Each country chooses its own strategy for combining these methods. For example, in Russia only livestock in small and individual farms is to be vaccinated whereas birds in poultry farms are not vaccinated, but are killed if either HPAI or LPAI is detected. 32 The genome of the quaranjaviruses consists of six segments of negative ssRNA. Segments 1À3 encode the proteins of a replicative polymerase complex (polymerase basic protein 2, or PB2; polymerase acidic protein, or PA; and polymerase basic protein 1, or PB1, respectively). The PB1 protein (polymerase 1 basic protein, RdRp) is one of the most conservative proteins of all viruses with a segmented RNA genome. The amino acid sequence similarity of the PB1 protein among the viruses of different genera in the Orthomyxoviridae family is 25À30%, on average, but the similarity of the functional domains of RdRp (pre-A, A, B, C, D, and E motifs) is 40À50% (Figure 8.110) .

The envelope glycoprotein GP (HA, segment 5) of the quaranjaviruses has a very low similarity to the homologous protein (HA, segment 4) of influenza viruses. However, it has some similarities tgo the surface glycoprotein of the baculoviruses. 1 The amino acid sequences of Thogotovirus genus members have about 20% identity with QRFV and TLKV.

Two other segments of the genome (segments 4 and 6) of the quaranjaviruses encode two proteins whose function is unknown. These proteins are probably structural proteins, which act as nucleocapsid (N) and matrix protein (M), respectively, but currently their function is not well known.

Other viruses of the Quaranjavirus genus have been found in South Africa, Nigeria, Egypt, Iran, Afghanistan, and Oceania. The quaranjaviruses are associated with Argasidae ticks (Argas arboreus, A. vulgaris, Ornithodoros capensis), which are obligate parasites of birds. 3 TLKV has been classified into the Quaranfil group of the Orthomyxoviridae family on the basis of its antigenic reactions. 4À14 Taxonomy. Like the other members of the Quaranjavirus genus, TLKV has a genome that consists of six ssRNA segments. 13 The PB1 protein amino acid sequence of TLKV has 86% and 84% identities with QRFV and JAV, respectively (Table 8 .61). The similarity of the PB2 and PA proteins of TLKV to those of Orf virus (ORFV) is 70%, on average.

The envelope glycoprotein (GP, segment 5) of the quaranjaviruses has very low similarity to the homologous protein (HA) of influenza viruses. However, it has some similarities to the surface glycoprotein of the baculoviruses. 4 The similarity of the GP of TLKV to that of QRFV is 72% nt and 80% aa (Table 8 .62). Segment 5 of TLKV has one ORF and encodes a protein with unknown function (524 aa). Its similarity to the same protein of QRFV is 85% aa. Segment 6 encodes a protein 266 aa long, which has no homology with any of the virus's proteins that are deposited in the database GenBank. The similarity of this protein in TLKV and the same protein in QRFV is 60%. Figures 8.110 and 8.112 show the results of phylogenetic analysis based on a comparison of PB1 and the envelope protein (GP and HA, respectively). On the phylogenetic trees, TLKV is grouped with QRFV and JAV within the Quaranjavirus genus. 13 Arthropod Vectors. Natural foci of TLKV associated with Argas vulgaris ticks in Kyrgyzstan are located below the northern border of the area of distribution of Argasidae ticks (43 % oN). This boundary coincides with the line of a frost-free period of 150À180 days a year and an average daily temperature above 20 for no less than 90À100 days per year. The ability of these ticks to withstand prolonged starvation (up to 9 years), as well as their long life cycle (25À30 years), polyphagia, and ability to transfer viruses transovarially, provides stability of the virus's natural foci. 1À3,15À18

Animal Hosts. TLKV was isolated from Argasidae ticks collected in the nesting burrows of birds. Complement-fixation testing of the birds from these colonies revealed that QRFV have been found in 2.6% of the human population. 11

The genus Thogotovirus currently includes four viruses: Thogoto virus (THOV), Dhori virus (DHOV), Araguari virus (ARGV), and Jos virus (JOSV). 1, 2 The viruses of Thogotovirus are arboviruses, transmitted mainly by Ixodidae ticks; therefore, the genus had previously been called Orthoacarivirus, to emphasize these viruses' association with ixodids (taxon Acari: order Parasitiformes, family Ixodidae). THOV was originally isolated from the ticks Rhipicephalus (Boophilus) decoloratus and Rh. evertsii collected from cattle in Thogoto forest, Nairobi, Kenya, in 1960. Subsequently, it was isolated from human, cows, camels, and ticks in many countries in Africa. 3, 4 The genome of the thogotoviruses consists of six segments of negative-polarity ssRNA that encode seven proteins. (Segment 6 encodes two forms of matrix protein.) 1, 2 The most conservative proteins of the replicative complex (PB1, PB2, PA) of thogotoviruses have 25À30% identity with those of the Influenza A virus genus.

History. Dhori virus (DHOV) was originally isolated from Hyalomma dromedarii ticks collected from camels in India. 1 DHOV has also been isolated in Egypt, Portugal, Russia, and Transcaucasia. 2À7 In Russia, several strains of DHOV were isolated from H. plumbeum ticks, Anopheles hyrcanus mosquitoes, and Lepus europaeus hares, all in the Volga River estuary. 5, 7 One strain of DHOV was isolated from the cormorant Phalacrocorax carbo in Maly Zhemchuzhnyi Island in the Caspian Sea (45 00 0 N, 48 18 0 E; Figures 8.113 and 8.114 ). 4 The prototypical strain of Batken virus (BKNV), LEIV-K306, was isolated from Hyalomma marginatum ticks collected from sheep near the town of Batken in Kyrgyzstan in April 1970. 8 Other strains of BKNV were isolated from a mixed pool of Aedes caspius and Culex hortensis mosquitoes in Kyrgyzstan 9 and from Ornithodoros lahorensis and Dermacentor marginatus ticks in Transcaucasia. 10 Antigenic studies showed that BKNV is closely related to DHOV, but differs from it. 8 Taxonomy. The similarity of the structural homologous proteins of the thogotoviruses (THOV, DHOV, ARGV, and JOSV) ranges from 25% (M-protein, segment 6) to 45% (NP, segment 5). The envelope protein HA (segment 4) has 35À45% identity, on average. The similarity of the nonstructural proteins (PB1, PB2, and PA) ranges from 60% to 74%.

BKNV has a high similarity to DHOV. The proteins are 96% (PB2, PA, NP, M) and 98% (PB1) identical. The similarity of the envelope protein HA of BKNV to that of DHOV is 90%, a percentage that explains the antigenic differences between these two closely related viruses. Because the homology of the other structural and nonstructural proteins of BKNV and DHOV is 96À98%, it can be concluded that BKNV is a variant of DHOV, typical to central Asia and Transcaucasia. A phylogenetic analysis based on a comparison of the PB1 and HA proteins is presented in Figures 8.110 and 8.112 .

Arthropod Vectors. Apparently, the main arthropod vector of DHOV and BKNV is Hyalomma sp. ticks-in particular, H. marginatum. DHOV has also been isolated from H. dromedarii, Dermacentor marginatus, and Ornithodoros lahorensis ticks. Rare isolations of DHOV and BKNV from mosquitoes (Anopheles hyrcanus, Aedes caspius, and Culex hortensis) suggest that they play some role in the circulation of these viruses. 9 Vertebrate Hosts. Antibodies to DHOV were found in 100% of camels, 19% of horses, and 2% of goats in the Indian state of Gujarat, where the virus was first isolated. Antibodies to BKNV were found in 1.0% of sheep and 1.3% of cattle in Kyrgyzstan. 9 Two strains of DHOV were isolated from a hare (Lepus europaeus) and a cormorant (Phalacrocorax carbo) in natural foci of the virus. 4, 5 The bird, from which DHOV was isolated on Maly Zhemchuzhnyi Island, was ill with respiratory failure, inability to fly, and loss of coordination 4 (Figure 8.114C) .

Human Disease. Several cases of disease caused by DHOV have been registered. 11 The disease occurred with fever, encephalitis (40%), headache, and weakness. Antibodies to DHOV were found in 4À9% of the population in the Volga River delta (in the south of Russia) and in 0.8% in the south of Portugal. 12 Antibodies to BKNV were found in the sera of 0.3% of the human population of Kyrgyzstan.

Five cases of laboratory infection were identified. 11 

The Togaviridae family consists of two genera (Alphavirus and Rubivirus) of enveloped RNA viruses. The virion of the togaviruses (70 nm) contains a core particle (40 nm) formed by a capsid protein and comprising a single-stranded, positive-sense genomic RNA 11,400À11,800 nt long. The lipid bilayer contains the heterodimers of two surface glycoproteins E1 and E2, which form an icosahedral surface of the virion. The genomic RNA has a cap structure at the 5 0 -and poly-A tail at the 3 0 -end, as well as two ORFs encoding nonstructural and structural proteins. The nonstructural proteins are encoded by the 5 0 -ORF (which occupies two-thirds of the genome), whereas the structural proteins are encoded by the subgenomic 3 0 -ORF. 1 Most viruses of the Alphavirus genus are arboviruses and can replicate in either a vertebrate host and or an invertebrate vector. 2, 3 The Rubivirus genus consists of one species-Rubella virus-that is transmitted by aerosol and is the causative agent of disease known as rubella. 4,5

The genome of the alphaviruses is a singlestranded RNA with positive polarity about 11,500 nt in length. The viral RNA has a cap at the 5 0 -end and a poly-A tail at the 3 0 -end. A large part of the genome of the alphaviruses (about two-thirds, beginning from one-third into the genome and extending to the 5 0 -end) encodes nonstructural proteins that form the viral replicative complex nsP1, nsP2, nsP3, and nsP4). Structural proteins (core, E3, E2, 6K, and E1) are translated from subgenomic RNA (26S RNA), which is formed in the process of replicating the virus and corresponds to the other one-third of the genome (Figure 8.115 ). 1 The alphaviruses can infect a wide range of vertebrates. Most of the alphaviruses are arboviruses and are associated with mosquitoes (genera Culex, Culiseta, Aedes, Coquillettidia, and Haemogogus) and birds, the latter of which can transfer viruses during migration. 2À4 Other vertebrate hosts of the alphaviruses are ruminants, reptiles, amphibians, and fish. 5, 6 The alphaviruses are divided into 10 antigenic complexes. Among the alphaviruses are dangerous pathogens of humans or animals, such as Eastern equine encephalitis virus (EEEV), Western equine encephalitis virus (WEEV), Sindbis virus (SINV), Chikungunya virus (CHIKV), and others. 7 History. CHIKV (family Togaviridae, genus Alphavirus, Semliki Forest group) is the etiological agent of a fever that is mortally dangerous to humans. This disease is accompanied by joint and muscle pains (right up to complete immobilization of the patient) and a two-wave course of the fever, together with a macu-larÀpapular rash emergency (usually during the second wave). 1 The etymology of the name "Chikungunya" is {chee-kungunyalac, which, in the Makonde local language, means "doubled up," owing to the severe joint pains.

CHIKV was originally isolated by R.W. Ross from the serum of a patient with fever during the decoding of an epidemic outbreak in Tanzania in FebruaryÀMarch 1956. 2À4 The close relation of CHIKV to Mayaro virus (MAYV), from the Semliki Forest group, was demonstrated in 1957 by serological methods. 5, 6 Distribution. CHIKV was also isolated in Cambodia in southeastern Asia in 1963, 7 in Hindustan in 1964, 8, 9 and in the eastern part of New Guinea in 2012. 10 The basic area over which CHIKV is distributed (Table 8. Taxonomy. CHIKV belongs to the Togaviridae family, Alphavirus genus, Semliki Forest group. On the basis of comparative analysis of the E1 gene, CHIKV was classified into three genotypes: A (Asian), CESA (centre, east, and south African), and WA (west African) 1,12À14 (Table 8. 

Vertebrate Hosts. Rodents, bats, and monkeys are the natural reservoir of CHIKV. 1,11À14,46 There is substantial evidence, that, in Africa, wild primates play an important role in the natural transmission cycle, but it is not clear whether infection in primates is incidental to or necessary for the maintenance of the virus. In Uganda, CHIKV was frequently isolated from Aedes africanus mosquitoes, which preferto feed on monkeys in the forest canopy. 47 Specific anti-CHIKV antibodies were found among chimpanzees (Pan troglodytes) in equatorial and savanna forests in the Democratic Republic of the Congo (Kinshasa) 48 and in savannas in southern Africa. Antibodies were found over a wide area in vervet monkeys (Cercopithecus aethiops) and baboons (Pipio ursinus), and in both species the virus could circulate in the blood for two to three days at high concentrations without evidence of illness. 49 So, wild animals could play an important role as amplifying hosts. 49 CHIKV was isolated in Dakar , Senegal, from bats, which developed viremia after experimental infection. But in India, inoculation of the virus into two species of fruiteating bats was followed by low virulence. 50, 51 Antibodies were found among donkeys, bats, and wild rodents in Africa 52 and among domestic animals in Asia. 49, 50 Inoculation of African strains into cattle, sheep, goats, and horses failed to produce viremia. Apart from chickens, adult fowl and several species of wild birds did not develop viremia after experimental infection. But experimental infection of vervet monkeys and baboons led to high viremia (up to 8 log 10 PFU/mL) during six days, which is sufficient for the infection of mosquitoes. 53 Arthropod Vectors. CHIKV is transmitted by bloodsucking mosquitoes. The main vectors for this virus during epidemics are Aedes aegypti and Ae. albopictus in urban regions and mosquitoes from the Aedes, Culex, and Coquillettidia genera in rural landscapes. 1,11À14,46 CHIKV has been multiply isolated from Ae. africanus, Ae. luteocephalus, Ae. furciferÀtaylori, Cx. fatigans, and Coq. fuscopenatta, all of which could preserve the virus and realize virus circulation in natural foci. 1, 54, 55 Epidemiology. A high level of viremia in humans (up to 8 log 10 PFU/mL) makes it possible for mosquitoes to transmit CHIKV from human to human 1 -a plausible reason that large epidemic outbreaks have been known in big cities of southern and southeastern Asia since the 1960s. 11,13,56À58 Beginning in the middle of the 1980s, epidemiological processes linked to CHIKV have intensified (Table 8 .63), although this fact could be explained by improvements in laboratory diagnostics: Previously, Chikungunya fever was often confused with dengue. In any event, CHIKVprovoked lethality has increased, in some cases up to 4.5%). 1, 59 Increases in the frequency of imported Chikungunya fever cases seen at the beginning of the twenty-first century (Table 8 .63) are most dangerous, especially when the possibility of CHIKV penetration into local mosquito populations is taken into account. Since 2006, imported cases of Chikungunya fever have become more frequent in Europe (Italy, 15, 38, 60, 61 Spain, 39 France, 35, 44, 62 Belgium, 35 Switzerland, 35 Germany, 35 the Czech Republic, 35 Norway 35 ); the Americas (Canada, 13 the United States, 35, 63 Brazil 44 ); eastern Asia (Hong Kong, 36 South Korea, 40 Japan 37,45 ); and Australia. 33 Outbreaks in Brazilian cities emerged with infections from Aedes aegypti, whereas in rural regions Aedes albopictus was the vector, introduced from southeastern Asia, 44 including Japan. 64 Imported Cases of Chikungunya Fever in Russia. A 59-year-old patient arrived in Russia September 22, 2013 , and suddenly fell ill, with a body temperature of 38.7 C. Antipyretic drugs were not effective. Early in the morning on September 24, 2013 , the patient was delivered to a Moscow infection hospital with a diagnosis of "fever with unknown etiology." The fever had mid-level severity, and the patient complained of shivering, headache, and asthenia. Hyperemia of the conjunctivae, papularÀhemorrhagic rash on the abdomen, and cruses were found.

A medical radiolograph (Figure 8 .116) of the lungs of the patient revealed decreased clarity at the back of the lung field and diffuse reticular pneumosclerosis in the right lower lobe pyramid, as well as local changes with expressed peribronchial and perivascular alterations. A round shadow was detected near (i.e., peribronchially to) the intermediate bronchus. The roots were intensified. The heart was enlarged at the left. Thus, the medical radiography portrait was consistent with rightside pneumonia with lymphadenopathy. Several peculiarities of the case were the bareness of clinical symptoms (pneumonia was diagnosed only via medical radiography), a rapid progression of changes in the lungs, and the absence of inflammation markers in the peripheral blood. Three days later, positive dynamics were detected: The basal parts of the right lung were restored to their previous level of clarity, although the shadow indicating a hypertrophic lymph node and right root broadening remained.

Bioprobes (blood swabs and nasopharyngeal swabs) were delivered to the D.I. Ivanovsky Institute of Virology. The absence of Influenza A and B viruses was established by RT-PCR. The strain CHIKV/LEIV-Moscow/1/2013 was isolated with the use of intracerebrally inoculated newborn mice and was identified with the help of a completegenome (GenBank ID: KF872195) nextgeneration sequence approach. Phylogenetic analysis (Figure 8 .117, Table 8 .64) revealed that the CHIKV/LEIV-Moscow/1/2013 strain belonged to an Asian genotype. This strain was deposited into the Russian State Collection of Viruses (deposition certificate N 1239 with a priority of November 11, 2013). 65 Serological methods revealed eight cases of imported Chikungunya fever that had previously been described in Russia: 66 from Indonesia, Singapore, India, the island of Réunion, and the Maldives Islands. The CHIKV/LEIV-Moscow/ 1/2013 strain was found to belong to the A-genotype, whereas most of the cases imported into Europe belong to the CESA genotype, reflecting the "bridge" role of Russia between Europe and Asia. The modern-day intensification of both international links and transport flows among countries increases the probability of imported cases of infection emerging. The penetration of Aedes aegypti and Aedes albopictus to the Russian Black Sea coast 1,67,68 suggests the emergence of seasonal outbreaks in the dynamically developing greater Sochi region as well.

History. Getah virus (GETV) was originally isolated in western Malaysia from Culex gelidus and Cx. tritaeniorhynchus mosquitoes. 1À3 This virus is widespread in southeastern Asia and in Australia. 3À5 The first isolation of GETV in Northern Eurasia was carried out by M.P. The Genome of GETV is 11,598 nt long. The strains of GETV, circulating in different geographical regions of northeastern and southeastern Asia, have a high level of similarity. 8À11 A pairwise comparison of complete genome sequences revealed that isolates from Malaysia, South Korea, China, Mongolia, Japan, and Russia have 96À98% nt identities, suggesting that the rate of GETV evolution is low. Phylogenetic analysis of the E2 gene ( Figure 8.118) is not conducive to dividing the GETV strains into distinct clusters.

Analyses of numerous strains isolated in Japan showed that genetic differences were determined by the time of isolation more than the place of isolation. 8 An analysis of 21 strains of GETV isolated in different regions of Russia revealed their high degree of similarity, but still, they could be divided into three groups on the basis of minimal differences. The first group comprises strains from tundra and for-estÀtundra in the Magadan region and the SakhaÀYakutia Republic in the north of Asia. The second group encompasses strains from leaf-bearing forests of Khabarovsk Krai. The third group consists of isolates from forestÀsteppe and steppe landscape belts of Khabarovsk Krai, the Republic of Buryatia, and Mongolia. 10, 12 Distribution. According to our data, 6,10,12À22 GETV is distributed over eastern Siberia and North Pacific physicogeographical lands (Figure 8.119) . The most intensive virus circulation was revealed in the steppe landscape belt of Mongolia, as well as in the mixed forests of Khabarovsk Krai and in the northern taiga of the Magadan region and the SakhaÀYakutia Republic. GETV circulation intensity is significantly lower in tundra and forestÀtundra landscapes, a phenomenon that could be explained by the temperature there.

GETV is the only member of the Alphavirus genus whose distribution extends to the rough climatic conditions of the high latitudes of Northern Eurasia. 18, 19 GETV has penetrated to the north of Asia from the overwintering places of birds, which regularly migrate by the east Asian flyway 17, 23 (Figure 3.2) . The distribution of the virus in the north coincides with that of Aedes mosquitoes, which are the effective vector of GETV.

GETV and closely related viruses are known outside of Northern Eurasia in Japan, various countries in southeastern Asia, and Australia. 1À3,5,24À29

Human Infection. The pathogenicity of GETV to humans has not yet been described. Nevertheless, the antigenically close RRV has been associated with large epidemic outbreaks of polyarthritis in Australia and Sarawak. 2, 4 Vertebrate Animal Infection. Symptomatic and subclinical infections of animals were reported in 1998 in Japan, where there was a large outbreak involving 722 racehorses. 30, 31 Among the clinical features seen were fever, rash on various parts of the body, and edema on the hind legs. Virus isolates were more similar to the prototypical Malaysian strain than to the Japanese Sagiyama strain. GETV has been implicated in illness and abortion or stillbirths in pigs. 32,33 Disease among horses was described in India. 34 Infection in cattle is usually subclinical. 3 Arthropod Vectors. GETV has been isolated from Culex gelidus, Cx. tritaeniorhynchus (Malaysia, Cambodia, China), Cx. bitaeniorhynchus, Anopheles amictus (Australia), Cx. vishnui (Philippines); the Sagiyama subtype of GETV was isolated from Cx. tritaeniorhynchus and Aedes vexans, as well as from pigs with fever, in Japan. 27, 35 Although their natural transmission cycle is not known in details, mosquitoes acquire GETV mainly while feeding on domestic mammals and fowl. There may also be a jungle cycle involving wild vertebrates. 5 The Bebaru subtype was isolated from Culex lophoceratomyia and Aedes spp. mosquitoes collected in mangrove swamp forests of western Malaysia. 32 The main vectors in Russia (i.e., in Northern Eurasia) are Aedes nigripes, Ae. communis, Ae. impiger, Ae. punctor, and Ae. excrucians. 18 4, 13 KFV was first noted in the summer of 1981 in the central and southwestern parts of Fennoscandia, including Russia, Finland, Sweden, and southern Norway (Figure 8 .120). 14 The prototypical strain LEIV-65A of KYZV was first isolated from Culex modestus mosquitoes collected in a colony of Ardeidae birds (herons) in Kyzylagach Reservation, located on the coast of Kyzylagach Bay in the Caspian Sea (39 10 0 N, 48 58 0 E; Figure 8 .120). 15 Taxonomy. On the basis of a comparison of a partial sequence of the E2 gene, isolates of SINV can be divided into five genotypes (Figure 8 .121). 9 Genotype I includes viruses from Europe and Africa, genotype II isolates from Australia and Oceania, and genotype III viruses from India and the Philippines. Together with the Chinese strain SINV XJ-160, KYZV was assigned to genotype IV. Genotype V consists of only the strain M78 from New Zealand. The strains of genotype I form two subclusters, one of which comprises SINVs from northern Europe and sub-Saharan Africa and the second of which consists of strains from the Mediterranean region (southern Europe, northern Africa, and the Middle East). 9 The genetic distance between the viruses of the different genotypes of SINV (e.g., between the European and Australian isolates) is not more than 23% nt (Table 8 .65). At the same time, SINVs isolated in the same geographic region are characterized by a high degree of similarity (Figure 8.122) . Thus, SINV strains isolated in Russia, Germany, Sweden(OCKV), and Finland have about 99% similarity (Table 8 .65). 3, 5, 6, 11 Babanki virus, which is from Cameroon, has 98% similarity to the European strains of SINV.

Despite the high degree of similarity among the different genotypes of SINV, known cases of human disease are caused only by strains of the EuropeanÀAfrican subcluster of genotype I (Karelian fever, a disease of Ockelbo, a disease of Babanki). KYZV has a high similarity (99%) to the Chinese isolate SINV XJ-160, isolated from Anopheles sp. mosquitoes in the Xinjiang Uighur Autonomous Region in the northwest of China. 16 The divergence of KYZV and XJ-160 from the European isolates of SINV is 18% nt and 7% aa of the entire genome sequence (Table 8 .65). The geographic isolation of KYZV and XJ-160 and their genetic divergence from the European and Australian isolates suggest that KYZV is a variant of SINV that is typical to Central Asia.

Distribution. SINV has been isolated in many regions of southern Europe, the Middle East, Africa, southeastern Asia, the Philippines, and Australia. 2, 17, 18 The African continent is almost all endemic for SINV: Strains are known from Egypt, the Republic of South Africa, Uganda, the Central African Republic, Sudan, Nigeria, and Zimbabwe. As for Asia, there are strains from Turkey, India, Malaysia, and the Philippines. In Australia, SINV strains were multiply isolated in the north of the continent. In Europe, SINV has been isolated in Sicily (Italy) and Slovenia. On the territory of the former USSR, SINV strains were multiply isolated in Belarus, Ukraine, Azerbaijan, Tajikistan, and western Siberia (in the areas around the central region of the Ob River valley). 17À19 . Vertebrate Hosts. The main vertebrate hosts of SINV are different species of birds, predominantly of the orders Passeriformes, Pelecaniformes, Ciconiiformes, and Anseriformes. SINV infection in birds can chronic, allowing them to transfer the virus during their seasonal migration. 17À20 Migratory birds play an important role in the wide distribution of this virus. SINV has been known to persist for as much as two months after experimental infection.

SINV strains have been multiply isolated from aquatic and semiaquatic birds in the delta of the Nile River in Egypt, from the white wagtail (Motacilla alba) and the common hill myna (Gracula religiosa) in India, and from the reed warbler (Acrocephalus scirpuceus) in the western part of Slovakia.

In Zimbabwe, SINV has been isolated from insectivorous bats of the Rhinolophidae and Hipposideridae families. 2 Occasionally, SINV has been isolated from rodents and amphibians.

On the territory of the former Soviet Union, SINV was originally isolated from a yellow herons (Ardeola ralloides) caught out of a bird colony in the southeastern part of Azerbaijan in 1968. Serological methods have revealed SINV circulation in the Astrakhan region among aquatic and semiaquatic birds, especially those of the orders Pelecaniformes (18%), Ciconiiformes (15%), and Anseriformes (11%). Neutralizing antibodies to SINV were found in coots (Fulica atra) (16.7%) from natural foci of the middle belt of the Volga River delta. In the Kuban River delta in Krasnodar Krai, specific anti-SINV antibodies were found among eight species of aquatic and semiaquatic birds, most frequently mallards (Anas platyrhynchos) and purple herons (Ardea purpurea). In Belarus, anti-SINV antibodies were detected in 4% of birds in the summer and in 0.4% in the fall. 21 Antibodies to SINV have been detected among farm animals (Table 8. cattle (17.5%) and horses (15.0%) in the middle belt of the Volga River delta.

Arthropod Vectors. SINV is closely associated with ornithophilic mosquitoes. In Egypt, this virus was isolated from Culex univittatus, Cx. antennatus, and Anopheles pharoensis; in Uganda, from Coquillettidia spp.; in Sarawak, (Malaysia), from Cx. bitaeniorhynchus; in Australia, from Cx. annulirostris, Aedes normanensis, and Ae. vigilax; in India, from Coq. fuscopennata; in Sudan, from Cx. quinquefasciatus; and in Europe, from Cx. pipiens, Cx. torrentium, Culiseta morsitans, Coq. richiardii, Ochlerotatus communis, Oc. excrucians, Ae. cinereus, and An. hyrcanus. 22, 23 According to our data, in the Volga River delta SINV is transferred by Culex pipiens in anthropogenic biocenoses and by Anopheles hyrcanus and Coquillettidia richiardii in natural ones. In the natural foci of the middle belt of the Volga delta, 1 strain can be isolated from approximately 3,800 An. hyrcanus or 3,300 Coq. Richiardii mosquitoes; in the low belt of the delta the ratio is 1 in about in a power less, and in anthropogenic biocenoses it is 1 strain per 1,500 Cx. pipiens mosquitoes. SINV strains from Gamasidae ticks (Ornithonyssus bacoti) in India and from Ixodidae ticks (Hyalomma marginatum) in Sicily (Italy) are known. 2 Productive experimental infections were described in the Argasidae ticks Ornithodoros savignyi and Argas persicus (although infected ticks did not transmit the virus during feeding). 23 Most likely, ticks do not play an important role in SINV circulation or as a reservoir for this virus.

Human Pathology. SINV causes acute fever in humans but has a favorable outcome. Antibodies to SINV are widely detected in human sera (Table 8 .66), although in eastern Siberia and the Far East cross-reactions with GETV (another member of the Semliki Forest serogroup) can take place.

The start of the disease is sudden. Clinical symptoms include fever, muscle and joint pain, and rash. Severe progressive arthritis of large joints could develop several years after the disease and could lead to disability. This pathology appears in 6À20% of citizens of endemic territories. Outbreaks of Sindbis fever in Egypt and Israel emerged at the same time as West Nile fever; hence, it is necessary to distinguish these infections in the laboratory.

A neurotropic virus isolated from Aedes mosquitoes caught in the Semliki forest

Virus taxonomy: classification and nomenclature of viruses: Ninth Report of the International Committee on Taxonomy of Viruses

Fields virology

Bunyavirus: structure and replication

Virus taxonomy: classification and nomenclature of viruses: Ninth Report of the International Committee on Taxonomy of Viruses

Recent discoveries of new hantaviruses widen their range and question their origins

A proposal for new criteria for the classification of hantaviruses, based on S and M segment protein sequences

Genetics of hantaviruses: implications to taxonomy

Hemorrhagic Fever with Renal Syndrome Virus and Related Viruses

Hemorrhagic fever with renal syndrome

Manuel of hemorrhagic fever with renal syndrome. Seoul: Korea Univ

Antigenic and molecular characterization of hantavirus isolates from China

Hantaviruses: ecology, molecular biology, morphology, pathogenesis and diagnostics of hantavirus infections

Hantavirus outbreak

Hantaviruses: genome structure, expression and evolution

Risk factors for human infection with Puumala virus, southwestern Germany

Investigation of virus evolution in the limits of the problems of biosafety and socially significant infections. Moscow: D.I. Ivanovsky Institute of Virology of RAMS

Characterization of Dobrava virus: a hantavirus from Slovenia, Yugoslavia

Epidemic hemorrhagic fever with renal syndrome in Yugoslavia

Genetic characterization of hantaviruses transmitted by the Korean field mouse (Apodemus peninsulae), Far East Russia

Complete genome sequence of an Amur virus isolated from Apodemus peninsulae in Northeastern China

Genetic variation of wild Puumala viruses within the serotype local rodent populations and individual animals

Phylogenetic relations of Western Siberian hantaviruses belonging to Tula and Puumala genotypes

Khabarovsk virus: a phylogenetically and serologically distinct hantavirus isolated from Microtus fortis trapped in Far-Eastern Russia

Development of serological assays for Thottapalayam virus, an insectivore-borne Hantavirus

Genetic analysis of Thailand hantavirus in Bandicota indica trapped in Thailand

Newfound hantavirus in Chinese mole shrew

Hantavirus infection in the Republic of Georgia

A new natural reservoir of hantavirus: isolation of hantaviruses from lung tissues of bats

Hantavirus isolation from birds

Handbook of virology: Viruses and viral infection of human and animals

Hemorrhagic fever with the renal syndrome

Hantavirus in bat

A new genetic variant of the PUUV virus from the Maritime Territory and its natural carrier red-grey vole Clethrionomys rufocanus

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Habitat factors associated with bank voles (Clethrionomys glareolus) and concomitant hantavirus in northern Sweden. Vector Borne Zoon Dis

Characterization of S gene of a strain of hantavirus isolated from Apodemus peninsulae in Heilongjiang Province

Hantaviruses and hantavirus infections

Hemorrhagic fever with renal syndrome caused by 2 lineages of Dobrava hantavirus

Discovery, clinical and etiological characteristic of hemorrhagic fever with renal syndrome in the subtropical zone of Krasnodar region

Ecological differences between different genovariants of Dobrava-Belgrade virus

Natural foci infections in low Volga Federal district and morbidity dynamics

Hantavirus infection in the Republic of Georgia

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Isolation of Tamdy virus from ticks Hyalomma asiaticum asiaticum in Kazakh SSR

Uspekhi nauki i tekhniki: Virology. Arboviruses and arboviral infection

Isolation of Tamdy virus (Bunyaviridae) pathogenic for man from natural sources in Central Asia, Kazakhstan and Transcaucasia

Migration of the birds and transduction of infection agents. Moscow: Nauka

Arboviral zoonoses of Northern Eurasia (Eastern Europe and the Commonwealth of Independent States)

Tamdy virus, strain LEIV-10224Az from ticks Hyalomma anatolicum from Apsheron district of Azerbaijan SSR. Deposition certificate of Russian State Collection of viruses

Taxonomy of previously unclassified Tamdy virus (TAMV) (Bunyaviridae, Nairovirus) isolated from Hyalomma asiaticum asiaticum Schü lce et Schlottke, 1929 (Ixodidae, Hyalomminae) in Central Asia and Transcaucasia

) Arachnoidea. Argas ticks (Argasidae)

Burana Virus (BURV)

Moscow: D.I. Ivanosky Institute of Virology

Isolation of new virus-Burana virus, from ticks Haemaphysalis punctata in the north climatic region of Kirgizia

Taxonomic status of Burana virus (BURV) (Bunyaviridae, Nairovirus, Tamdy group), isolated from ticks Haemaphysalis punctata Canestrini et Fanzago, 1877 and Haem. concinna Koch, 1844 (Ixodidae, Haemaphysalinae) in Kyrgyzstan

Virus taxonomy: Ninth Report of the International Committee of Taxonomy of Viruses

Identification of a novel C-terminal cleavage of Crimean-Congo hemorrhagic fever virus PreGN that leads to generation of an NSM protein

Crimean-Congo hemorrhagic fever virus glycoprotein proteolytic processing by subtilase SKI-1

Structure of Crimean-Congo hemorrhagic fever virus nucleoprotein: superhelical homo-oligomers and the role of caspase-3 cleavage

Itogi nauki i techniki. Virology. Moscow: USSR Academy of sciences

Fields virology

Nucleotide sequence analysis of the large (L) genomic RNA segment of Bunyamwera virus, the prototype of the family Bunyaviridae

Identification of nonstructural proteins encoded by viruses of the Bunyamwera serogroup (family Bunyaviridae)

M viral RNA segment of bunyaviruses codes for two glycoproteins, G1 and G2

The Nterminus of Bunyamwera orthobunyavirus NSs protein is essential for interferon antagonism

NSs protein of Rift Valley fever virus induces the specific degradation of the double-stranded RNA-dependent protein kinase

Role of the NSs protein in the zoonotic capacity of Orthobunyaviruses

bunyaviruses: sequence determination and analysis

Mosquito-borne viruses in Europe

Relationships of bunyamwera group viruses by neutralization

International catalogue of arboviruses including certain other viruses of vertebrates

The Chalovo virus-the second virus isolated from mosquitoes in Czechoslovakia

The isolation of the Chalovo virus from the mosquitoes of the group Anopheles maculipennis in Southern Moravia

Investigation of biological properties of Olyka virus isolated from mosquitoes (Culicidae) in Western Ukraine

Isolation of arboviruses from birds in Western Ukraine

Persistence of Batai virus, strain Olyka, from bird. Virusy i Virusnye Zabolevaniya

The ecology of Batai virus in Danube delta

Molecular characterization of Chittoor (Batai) virus isolates from India

Batai and Ngari viruses: M segment reassortment and association with severe febrile disease outbreak in East Africa

Complete genome analysis of Batai virus (BATV) and a new Anadyr virus (ANADV) of Bunyamwera group (Bunyaviridae, Ortho-bunyavirus) isolated in Russia

Isolation of Batai virus (Bunyaviridae, Bunyavirus) from the blood of suspected malaria patients in Sudan

Isolation of Batai virus from sentinel domestic pig from Kolar district in Karnataka State

Bunyamwera arbovirus supergroup in Finland. A study on Inkoo and Batai viruses

Arboviruses and arbovirus infections

Arboviral zoonoses in Western Europe

Uberwintering des Chalovo Virus in experimentall infizierten Weibach von Anopheles maculipennis messeae Fall

Distribution of arboviruses in the Volga territory

Handbook of virology: Viruses and viral infection of human and animals

Populational interactions of West Nile and other arbovirus infections with arthropod vectors, vertebrates and humans in the middle and low belts of Volga delta

Complex environmental and virological monitoring in the Primorje Territory in

Experimental demonstration of the Batai virus maintenance in hibernating females of Anopheles maculipennis

Arboviruses of the California complex of the Bunyamwera group

Arboviruses of the California complex of the Bunyamwera group

Pathogenic properties of the LEIV-23 Astrakhan strain of Batai virus for primates

Isolation of 2 human strains of Ilesha virus in the Central African Republic

Ilesha virus: a new aetiological agent of haemorrhagic fever in Madagascar

Molecular-genetic analysis of the Batai virus strains isolated from mosquitoes in Volgograd Region of the Russian Federation

California Encephalitis Complex Viruses: Inkoo Virus, Khatanga Virus, Tahyna Virus 1. Casals J. Immunological relationship between Tahyna and California encephalitis viruses

International catalogue of arboviruses including certain other viruses of vertebrates

Isolation of viruses from mosquitoes collected at Lumbo, Mozambique. I. Lumbo virus, a new virus isolated from Aedes (Skusea) pembaensis Theobald

The Tahyna virus a virus isolated from mosquitoes in Czechoslovakia

Mosquito-borne viruses in Finland

Arboviruses in Finland. IV. Isolation and characterization of Inkoo virus, a Finnish representative of the California group

Isolation of California encephalitis virus from the blood of a snowshoe hare (Lepus americanus) in western Montana

Phylogenetic analysis of the nucleotide sequences of Khatanga virus strains, the new representative of California encephalitis serocomplex, isolated in different regions of the Russian Federation

Circulation of viruses of the California serocomplex (Bunyaviridae, Bunyavirus) in the central and southern parts of the Russian plain

Characteristic of the new Khatanga virus genotype

Fields virology

Isolation of Tahyna virus from Culex pipiens mosquitoes in Romania

Izolierung des Tahyna Virus aus Stechmucken in Isterreich

Untersuchungen uber die Okologie des Tahyna Virus

Feldutersuchungen uber die Bedentung des Igels (Erinaceus europaeus roumanicus Barret-Hamilton) im Zykles des Tahyna Virus

Isolation of Tahyna virus from field collected Culiseta annulata (Schrk.) larvae

California serogroup virus infections in the Ryazan region of the USSR

California serogroup virus infections in Wisconsin domestic animals

Isolation of Tahyna virus in the south of France

The isolation of the Tahyna virus from the mosquito Aedes vexans in Southern Moravia

Study of arboviruses in the region of Most from 1981 to 1982. Isolation of Tahyna viruses

Nachweis des Tahyna Virus beistechmucken in zwei verschiedenen europaischen Naturherden

Tahyna virus natural focus in Southern Moravia

California encephalitis group viruses isolated from mosquitoes collected in Southern and Arctic Norway

Reassortment of La Crosse and Tahyna bunyaviruses in Aedes triseriatus mosquitoes

Epidemiology and ecology of the California serogroup viruses

First isolation of La Crosse virus from naturally infected Aedes albopictus

Introduction of Aedes albopictus into a La Crosse virus-enzootic site in Illinois

Laboratory demonstration of transovarial transmission of Tahyna virus in Aedes vexans and the role of this mechanism in overwintering of this arbovirus

Distribution of viruses from the Californian encephalitis serogroup (Bunyaviridae, Bunyavirus) in the northern expanses of Russia

Viruses of Californian serogroup and etiologically linked diseases: clinic-epidemiological characteristics, geographical distribution, methods of virological and serological diagnostics

Atlas of distribution of natural foci virus infections on the territory of Russian Federation. Moscow: SMC MPH RF Publ

Isolation of Tahyna virus from Anopheles hyrcanus mosquitoes in Kyzylagach preserve, South-Eastern Azerbaijan

Necrotizing panencephalitis in puppies infected with La Crosse virus

Experimental transmission of Tahyna virus (California group) to wild rabbits (Oryctolagus cuniculus) by mosquitoes

Moscow: Meditsina;1989p

California group viral infection

The incidence risk, clustering and clinical presentation of La Crosse virus infections in the eastern United States

Crosse virus in Aedes albopictus mosquitoes

Clinical aspects of La Crosse encephalitis: neurological and psychological sequelae

Isolation of Tahyna virus from Aedes vexans mosquitoes in Serbia

Canine La Crosse viral meningoencephalomyelitis with possible public health implications

Handbook of virology: Viruses and viral infection of human and animals

Arboviruses and arbovirus infections

Natural focus of Tahyna virus in South Moravia

Arboviruses of the California complex and Bunyamwera group in Finland

Isolation of California antigenic group viruses from patients with acute neuroinfection syndrome

Isolation of Tahyna virus (California antigenic group, family Bunyaviridae) from the blood of febrile patients in the Tadzhik SSR

Natural virus foci in high latitudes of Eurasia

Circulation of California encephalitis complex viruses in the northwestern Russian plain

Tasclische Bild der Tahina Virus (California Gruppe) infectionenbei

Acute human infection caused by Tahyna virus

Tahyna virus-neutralization antibodies in patients in Southern Moravia

Meningoencephalit virus Tahyna

Clinical manifestation of Tahyna virus infection in patients in Eastern Slovakia

Mosquito-borne arboviruses in Norway: further isolations and detection of antibodies to California encephalitis viruses in human, sheep and wildlife sera

The possible presence of Tahyna (Bunyaviridae, California serogroup) virus in the People's Republic of China

Arboviruses as aethiological agents of encephalitis in the Peoples Republic of China

Tahyna virus and human infection

Equine encephalitis caused by snowshoe hare (California serogroup) virus

The growing importance of California arboviruses in the etiology of human disease

Medically important arboviruses of the United States and Canada

Significance of viruses of antigen complex of California encephalitis in pathology

The clinico-laboratory characteristics of cases of diseases connected with viruses of the California encephalitis complex in the inhabitants of Moscow

Signs and symptoms of infections caused by California serogroup viruses in humans in the USSR

Diseases associated with viruses of the California encephalitis serogroup, in Russia

Khurdun virus, a presumably new RNA-containing virus associated with coots (Fulica atra), isolated in the Volga river delta

Screening of birds in the Volga delta (Astrakhan region, 2001) for the West Nile virus by reverse transcriptionpolymerase chain reaction

West Nile virus and other zoonotic viruses in Russia: examples of emerging-reemerging situations

Virus taxonomy: classification and nomenclature of viruses : Ninth Report of the International Committee on Taxonomy of Viruses

The Khurdun virus (KHURV): a new representative of the Orthobunyavirus (Bunyaviridae)

Rift Valley fever virus L segment: correction of the sequence and possible functional role of newly identified regions conserved in RNA-dependent polymerases

Cytoplasmic tails of bunyavirus Gn glycoproteins-Could they act as matrix protein surrogates?

Cytoplasmic tails of hantavirus glycoproteins interact with the nucleocapsid protein

Viruses in the Anopheles A, Anopheles B, and Tete serogroups in the Orthobunyavirus genus (family Bunyaviridae) do not encode an NSs protein

Fields virology

Virus taxonomy: classification and nomenclature of viruses : Ninth Report of the International Committee on Taxonomy of Viruses

Complete nucleotide sequence of the M RNA segment of Uukuniemi virus encoding the membrane glycoproteins G1 and G2

1 Bhanja Virus and Razdan Virus (var. Bhanja virus)

Bhanja virus: a new arbovirus from ticks Haemaphysalis intermedia Warburton and Nuttall

Isolation of Bhanja virus from ticks of the genus Haemaphysalis in southeast Bulgaria and presence of antibodies in pastured sheep

Isolation of Bhanja virus from Haemaphysalis ticks in Italy

Isolation of Bhanja virus from ticks in Yugoslavia

Palma virus, a new Bunyaviridae isolated from ticks in Portugal

Forecariah virus, a new representative of the Bhanja antigenic group, isolated in the Republic of Guinea

Kisemayo virus, a representative of the Bhanja antigenic group

Numerical comparative serology of the Bhanja antigenic group (Bunyaviridae)

Arboviral zoonoses of Asia

Razdan virus, a new ungrouped bunyavirus isolated from Dermacentor marginatus ticks in Armenia

International Catalogue of Arboviruses Including Certain other Viruses of Vertebrates

Geographic distribution of Bhanja virus

Experimental pathogenicity of Bhanja virus

Molecular-genetic characterization of the Bhanja virus (BHAV) and the Razdan virus (RAZV) (Bunyaviridae, Phlebovirus) isolated from the ixodes ticks Rhipicephalus bursa (Canestrini and Fanzago, 1878) and Dermacentor marginatus (Sulzer, 1776) in Transcaucasus

Genetic characterization of Bhanja virus and Palma virus, two tick-borne phleboviruses

Characterization of the Bhanja serogroup viruses (Bunyaviridae): a novel species of the genus Phlebovirus and its relationship with other emerging tick-borne phleboviruses

A novel bunyavirus in China

Fever with thrombocytopenia associated with a novel bunyavirus in China

Characterization of the Uukuniemi virus group (Phlebovirus: Bunyaviridae): evidence for seven distinct species

Rift Valley fever virus L segment: correction of the sequence and possible functional role of newly identified regions conserved in RNA-dependent polymerases

Gouleako virus isolated from West African mosquitoes constitutes a proposed novel genus in the family Bunyaviridae

A new phlebovirus associated with severe febrile illness in Missouri

Biogeography of tick-borne Bhanja virus (Bunyaviridae) in Europe

Serological survey of domestic animals for tick-borne encephalitis and Bhanja viruses in northeastern Hungary

Ecological and nosological study of tick-borne arboviruses in Senegal. II. Experimental study of the pathogenicity of the Bhanja virus in small domestic ruminants

Experimental infection of sheep with Bhanja virus

Experimental pathogenecity of Bhanja virus for lambs of different infection routes

Experimental pathogenicity of Bhanja virus for white mice and Macaca mulatta monkeys

Human infection with Bhanja virus

Incidence of hemagglutination-inhibiting antibodies for Bhanja virus in humans along the north-west border of Yugoslavia

First natural clinical human Bhanja virus infection

Gissar virus-a new virus of family Bunyaviridae, isolated from argases ticks Argas vulgaris Fil. in Tajikistan

The strain 5595 of Gissar virus. Deposition certificate of Russian State Collection of viruses

Arboviral zoonoses of Northern Eurasia (Eastern Europe and the Commonwealth of Independent States)

Handbook of zoonoses. Section B: Viral

Molecular genetic characterization of Gissar virus (GSRV) (Bunyaviridae, Phlebovirus, Uukuniemi group), isolated from ticks Argas reflexus Fabricius, 1794 (Argasidae), collected in dovecote in Tajikistan

Isolation in Southern France and characterization of new tick-borne viruses related to Uukuniemi: grand Arbaud and Ponteves

Phlebovirus: Bunyaviridae): evidence for seven distinct species. Characterization of the Uukuniemi virus group

Itogi nauki i techniki. Virology. Arboviruses and arboviral infections

Arachnoidea. Argas ticks (Argasidae)

Khasan virus, a new ungrouped bunyavirus isolated from Haemaphysalis longicornis ticks in the Primorie region

Electron microscopy of the Uukuniemi virus, an ungrouped arbovirus

International catalogue of arboviruses including certain other viruses of vertebrates

The taxonomy of the Khasan virus (KHAV), a new representative of Phlebovirus genera (Bunyaviridae), isolated from the ticks Haemaphysalis longicornis (Neumann, 1901) in the Maritime territory (Russia)

Characterization of the Uukuniemi virus group (Phlebovirus: Bunyaviridae): evidence for seven distinct species

Fever with thrombocytopenia associated with a novel bunyavirus in China

A new phlebovirus associated with severe febrile illness in Missouri

and northeastern China and USSR, and its parthenogenetic and bisexual populations (Ixodoidea, Ixodidae)

The ecology, genetic diversity, and phylogeny of Huaiyangshan virus in China

Sandfly Fever Naples Virus and Sandfly Fever Sicilian Virus

Virus taxonomy. Ninth Report of International Committee of Taxonomy of viruses

The arthropod-borne viruses of Vertebrate

Studies on the antigenic relationship among phleboviruses

Weitere unterschunget uber das pappataci-frieber

Viral on Rickettsae infections of man

Experimental studies on Phlebotomus (pappataci, sandfly) fever during World War II

Isolation and characterization of arboviruses from Almirante, Republic of Panama

Central nervous system involvement during infection by Phlebovirus toscana of residents in natural foci in central Italy (1977À1988)

International catalogue of arboviruses including certain other viruses of vertebrates

International catalogue of arboviruses including certain other viruses of vertebrates

Sandfly fever virus outbreak in Cyprus

Novel Phlebovirus in febrile child

Cocirculation of 2 genotypes of Toscana virus, southeastern France

Sandfly fever in Central Asia and Afganistan

Arboviral zoonoses of Northern Eurasia (Eastern Europe and the common wealth of Independent States)

Characterization of the Sandfly fever Naples species complex and description of a new Karimabad species complex (genus Phlebovirus, family Bunyaviridae)

Toscana virus isolated from sandflies

Sandfly fever Sicilian virus

Arboviral zoonoses of Western Europe

Phlebotomus fever

Serological studies on the epidemiology of sandfly fever in the Old World

Studies on the epidemiology of sandfly fever in Iran. I. Virus isolates REFERENCES II. ZOONOTIC VIRUSES OF NORTHERN EURASIA: TAXONOMY AND ECOLOGY obtained from Phlebotomus

Emergence of Toscana virus in Europe

High prevalence rates of antibody to three sandfly fever viruses (Sicilian, Naples, and Toscana) among Cypriots

Toscana virus infection imported from Elba into Switzerland

Sandfly fever due to Toscana virus: an emerging infection in southern France

Toscana virus infection in American traveler returning from Sicily

Prevalence of Toscana virus antibodies in residents of two Ionian islands

Toscana virus and acute meningitis

Studies on the epidemiology of sandfly fever in Iran. II. The prevalence of human and animal infection with five phlebotomus fever virus serotypes in Isfahan province

Imported aseptic meningitis due to Toscana virus

Isolation of phlebotomus (sandfly) fever virus from sandflies and humans during the same season in Aurangabad District, Maharashtra State, India

Genetic variability of the M genome segment of clinical and environmental Toscana virus strains

The etiology of phlebotomus fever

Zur Pathologie und Therapie einer Eigenthumlichen endemischen Krankheits-form

Isolation of some viruses other than typical tickborne encephalitis viruses from Ixodes ricinus ticks in Finland

International catalogue of arboviruses and some others viruses of vertebrates

Isolation and study of Sumakh virus, a member of the Uukuniemi group

Features of Uukuniemi group Sumah virus, isolated from trush Turdus merula in southern-eastern part of Azerbaijan. Problems of medical virology

Ecology of Viruses., 1. Moscow: USSR Academy of Medical Sciences

Arboviruses of high latitudes in the USSR

Natural virus foci in high latitudes of Eurasia

Isolation of three Uukuniemi virus strains from ticks in Volgograd district

Natural foci of arboviruses, associated with the birds in USSR

Detection of Uukuniemi virus in Belorussia

Isolation of Uukuniemi group viruses from arthropods and birds in Chernovitskay district

Studies of Uukuniemi virus strains, isolated in Lithuanian SSR and Estonian SSR

Ecological sounding of the USSR territory for natural foci of arboviruses

Actual problems of virology and natural-foci viral infection

Experimental study of relationships between Uukuniemi virus and Ixodes ricinus ticks

Investigation of arbovirus infections in Belarus and other western areas of the USSR

Isolation of a presumably new virus from unengorged Ixodes ricinus ticks

Uukuniemi virus in western Slovakia and northern Moravia

Less known arboviruses of Central Europe. Rozpravy CSAV (Praha) Mat Prir Vedy

Isolation of arbovirus strains of Uuruniemi type in Poland

Zaliv Terpeniya" virus, a new Uukuniemi group arbovirus isolated from Ixodes (Ceratixodes) putus Pick.-Camb. 1878 on Tyuleniy Island (Sakhalin region) and Commodore Islands (Kamchatsk region)

International Catalogue of arboviruses and some others viruses of vertebrates

Isolation of Terpeniye Gulf arbovirus from Ixodes (Ceratixodes) putus Pick-Cambr., 1878 ticks in Murmansk Province

Ecology of tick-borne viruses in colonies of birds in the USSR

Tick-and mosquito-associated viruses in Norway. Oslo: Nat Inst Publ Hlth

Characterization of the Uukuniemi virus group (Phlebovirus: Bunyaviridae): evidence for seven distinct species

About the species of Ixodes persulcatus (Parasitiformes, Ixodidae) group

Uukuniemi virus in small rodents

New isolates of arboviruses in Ukraine and their biological characteristics

Isolation of Uukuniemi arbovirus from Coccothraustes coccothraustes and Streptopelia turtur in the Carpathian area and western Ukrainian Polesye

Passerine birds in the ecology of Uukuniemi virus

Arboviruses in Finland. II. Isolation and characterization of Uukuniemi virus, a virus associated with ticks and birds

Antibodies against some arboviruses in personswith various neuropathies

Investigation of the role of Uuruniemi virus human pathology

Serological examination of the population from the endemic area of the tick-borne encephalitis virus (TBEV) and Uukuniemi virus (UKV)

Komandory Virus and Rukutama Virus (var. Komandory virus)

Arboviral zoonoses of Northern Eurasia (Eastern Europe and the commonwealth of independent states)

Genetic characteristic of a new Komandory virus (KOMV; Bunyaviridae, Phlebovirus) isolated from ticks Ixodes uriae, collected in guillemot (Uria aalge) nesting sites on Komandorski Islands

Paramushir virus (PMRV) (Sakhalin group, Nairovirus, Bunyaviridae) and Rukutama virus (RUKV) (Uukuniemi group, Phlebovirus, Bunyaviridae), isolated from the obligate parasites of colonial sea-birdsticks Ixodes (Ceratixodes) uriae, White 1852 and I. signatus Birulya, 1895 in water area of sea of Okhotsk and Bering sea

Seroepidemiological survey for Bunyaviridae and certain other arboviruses in Pakistan

Characterization of the Uukuniemi virus group (phlebovirus: bunyaviridae): evidence for seven distinct species

Zaliv Terpeniya" virus, a new Uukuniemi group arbovirus isolated from Ixodes (Ceratixodes) putus Pick.-Camb. 1878 on Tyuleniy Island (Sakhalin region) and Commodore Islands (Kamchatsk region)

Genetic characterization of Zaliv Terpeniya virus (ZTV, Bunyaviridae, Phlebovirus, Uukuniemi serogroup) strains

1852, obligate parasites of Alcidae birds, in high latitudes of Northern Eurasia and mosquitoes Culex modestus Ficalbi, 1889 in subtropics Transcaucasus

Tuleniy virus. A new Group B arbovirus isolated from Ixodes (Ceratixodes) putus Pick.-Camb. 1878 collected on Tuleniy Island, Sea of Okhotsk

Sakhalin" virus-a new arbovirus isolated from Ixodes (Ceratixodes) putus Pick.-Camb. 1878 collected on Tuleniy Island, Sea of Okhotsk

Okhotskiy" virus, a new arbovirus of the Kemerovo group isolated from Ixodes (Ceratixodes) putus Pick.-Camb. 1878 in the Far East

Ecology of tick-borne viruses in colonies of birds in the USSR

Virus taxonomy: 9th Rep Intern Comm Taxonomy of Viruses

Flaviviridae: the viruses and their replication

Phylogeny of the genus Flavivirus

Flavivirus genome organization, expression, and replication

Persistent emergence of dengue

Yellow fever: the recurring plague

Globalization, land use, and the invasion of West Nile virus

Spring-summer fever in Omsk region

Biological and epizootological characteristics of natural focies of Omsk hemorrhagic fever in Western Siberia

Materials for epidemiology, etiology and prophylaxis of spring-summer fever in some districts of Omsk region

Three years of investigation of Omsk hemorrhagic fever (1946À1948)

For the results of expedition of the Institute of neurology on the investigation of Omsk hemorrhagic fever (OHF)

Isolation and investigation of strains of the causative agent of Omsk haemorrhagic fever

Virological characteristics of Omsk haemorrhagic fever and tick-borne encephalitis natural foci in Western Siberia [Thesis of medical doctor dissertation

Epidemiological and virological characteristics of natural focies of Omsk hemorrhagic fever (OHF)

Transmission of Omsk haemorrhagic fever by ticks

Genetic characterization of tick-borne flaviviruses: new insights into evolution, pathogenetic determinants and taxonomy

Molecular determinants of antigenicity of two subtypes of the tick-borne flavivirus haemorrhagic fever virus

Analysis of the complete genome of the tick-borne flavivirus Omsk hemorrhagic fever virus

Omsk haemorrhagic fever (current status of the problem)

The modern state of epidemic process and epidemiological characteristics of Omsk haemorrhagic fever foci. In: The problems of infectious pathology. Omsk

On the possibility of mixed infection of vertebrates and arthropods of tick-borne encephalitis virus and Omsk haemorrhagic fever virus

Handbook of virology. Viruses and viral infection of human and animals

Omsk hemorrhagic fever: sum of data (1946À2013)

Isolation of Omsk hemorrhagic fever virus from Aedes mosquitoes in Barabinsk lowland (Zdvinsk district)

Taxons of blood-sucking mosquitoes in the ecology of arboviruses in Western Siberia. In: Arboviruses. Materials of Session of Problem Commission. Tallinn

Bloodsucking mosquitoes as vectors for Omsk hemorrhagic fever virus. In: Natural foci human diseases. Omsk

About possible role of blood-sucking mosquitoes in the transmission of Omsk hemorrhagic fever virus. Problems of medical virology. Arboviruses

Nature of the world: landscapes. Moscow: Mysl

Omsk hemorrhagic fever

Clinic and epidemiological characteristics of Omsk hemorrhagic fever

Clinic and epidemiological characteristics of Omsk hemorrhagic fever

Omsk haemorrhagic fever virus: epidemiological and clinical aspects

Effectiveness of virazol, realdiron and interferon inductors in experimental Omsk hemorrhagic fever

Powassan virus: isolation of virus from a fatal case of encephalitis

Powassan encephalitis

Powassan virus: field investigations in Northern Ontario

Isolation of a virus closely related to Powassan virus from Dermacentor andersoni collected along North Cache la Poudre River

Isolation of the Powassan virus from Haemaphysalis neumanni Donitz, 1905 ticks in the Maritime Territory

Complete genomic sequence of Powassan virus: evaluation of genetic elements in tick-borne versus mosquito-borne flaviviruses

Virus taxonomy. Ninth Report of the International Committee on Taxonomy of Viruses

Phylogeny of North American Powassan virus

Characterization of Powassan viruses from Far Eastern Russia

Handbook of zoonoses. Section B: Viral

Powassan virus: persistence of virus activity during 1966

California encephalitis and Powassan virus activity in British Columbia

The significance of Ixodes ticks in the southern Far East in the circulation of Powassan virus

Isolation of viruses from natural sources in USSR

Powassan virus in Ixodes cookei and Mustelidae in New England

The role of wild murine rodents in the selection of different strains of tick-borne encephalitis and Powassan viruses

Role of Powassan virus in the etiological structure of tickborne encephalitis in the Primorsky krai

The clinicoepidemiological characteristics of Powassan encephalitis in the southern Soviet Far East

Pathomorphology of experimental infection caused by Powassan virus isolated in the Primorsky Territory

Tick-Borne Encephalitis Virus and Alma-Arasan Virus (var. Tick-borne encephalitis virus)

Natural foci of transmissible infections. Moscow/Leningrad: Nauka

Spring (spring-summer) endemic tick-borne encephalitis

Antigenic classification and taxonomy of flaviviruses (family Flaviviridae) emphasizing a universal system for the taxonomy of viruses causing tickborne encephalitis

Antigenic relationships between flaviviruses as determined by cross-neutralization tests with polyclonal antisera

Sequence analysis and genetic classification of tick-borne encephalitis viruses from Europe and Asia

Arboviruses in birds captured in Slovakia

Molecular epidemiology of tick-borne encephalitis virus: cross-protection between European and Far Eastern subtypes

Antigenic similarity of central European encephalitis and louping-ill viruses

Monoclonal antibodies to tick-borne encephalitis (TBE) virus: their use for differentiation of the TBE complex viruses

Migration of birds and the transfer of the infectious agents. Moscow: Nauka

Arboviruses in Kazakhstan region [Doctor medical sciences dissertation

Arboviruses and arbovirus infections

Genetic characteristics of Powassan virus (POWV) isolated from Haemaphysalis longicornis ticks in Primorsky krai and two strains of Tick-borne encephalitis virus (TBEV) (Flaviviridae, Flavivirus): Alma-Arasan virus (AAV) isolated from Ixodes persulcatus in Kazakhstan and Malyshevo virus (MALOV) isolated from Aedes vexans mosquitoes in Khabarovsk krai

Investigation of virus evolution in the limits of the problems of biosafety and socially significant infections. Moscow

The Siberian and Far-Eastern subtypes of tick-borne encephalitis virus registered in Russia's Asian regions: genetic and antigen characteristics of the strains

Molecular epidemiology of tick-borne encephalitis. Irkutsk

Biochorological structure of species (on the example of taiga tick)

Tick-borne spring-summer encephalitis in the wider Ural area

Tick-borne encephalitis

Tick-borne encephalitis virus in ticks in Finland, Russian Karelia and Buryatia

Infection rate of the ticks in different landscapes of Altai krai

Studies on biological properties of viruses of tick-borne encephalitis complex in tissue culture

Epidemiological features of biphasic virus of meningoencephalitis

The geographical distribution of genetic variants of the tickborne encephalitis virus

Arboviruses in Finland. I. Isolation of tick-borne encephalitis (TBE) virus from arthropods, vertebrates, and patients

Tick-borne encephalitis virus in wild rodents in winter

Epidemiology of tick-borne encephalitis in Sweden 1956À1989: a study of 1116 cases

Prevalence of tick-borne encephalitis virus in Ixodes ricinus ticks in northern Europe with particular reference to Southern Sweden

Tick-borne encephalitis

Detection of specific IgG antibodies in blood donors and tickborne encephalitis virus in ticks within a non-endemic area in southeast Norway

Tick-borne encephalitis virus, Norway and Denmark

Recovery of the tick-borne encephalitis virus from the blood and milk of subcutaneously infected sheep

Full genome sequences and preliminary molecular characterization of three tick-borne encephalitis virus strains isolated from ticks and a bank vole in Slovak Republic

Tick-borne encephalitis associated with consumption of raw goat milk

The ticks of the natural focus of tick-borne encephalitis of sheep and man in the Rhodope Mountains (Bulgaria)

Seroepidemiological and ecological investigations of natural foci of tick-borne encephalitis in Hungary

Studies on the occurrence of tick-borne encephalitis in Hungary

Cross-border surveillance differences: tick-borne encephalitis and lyme borreliosis in the Czech Republic and Poland

Chorea and tick-borne encephalitis

Detection and genetic characterization of tick-borne encephalitis virus (TBEV) derived from ticks removed from red foxes (Vulpes vulpes) and isolated from spleen samples of red deer (Cervus elaphus) in Croatia

Vectors of tick-borne diseases and epidemiological situation in Latvia in 1993À2002

Molecular epidemiology of tick-borne encephalitis virus in Ixodes ricinus ticks in Lithuania

Characterization of tick-borne encephalitis virus from Estonia

Natural focies of tick-borne encephalitis in Baltic. IV. Further investigation of the areal of fleas. Deponent of VINITI

Central European encephalitis in the Federal Republic of Germany

Factors affecting patterns of tick parasitism on forest rodents in tickborne encephalitis risk areas

Tick-borne encephalitis (TBE) in Germany-epidemiological data, development of risk areas and virus prevalence in fieldcollected ticks and in ticks removed from humans

Tick-borne encephalitis in Europe and beyond-the epidemiological situation as of

Complete Genome Sequence of Tick-Borne Encephalitis Virus Strain A104 Isolated from a Yellow-Necked Mouse (Apodemus flavicollis) in Austria

Patterns of tick-borne encephalitis virus infection in rodents in Slovenia

Tickborne encephalitis, southwestern France

Tick-borne encephalitis in Friuli Venezia Giulia, northeastern Italy

Tickborne encephalitis virus, northeastern Italy

Seasonal dynamics of Ixodes ricinus in a 3-year period in northern Spain: first survey on the presence of tick-borne encephalitis virus

Phylogenetic and virulence analysis of tick-borne encephalitis viruses from Japan and far-Eastern Russia

Molecular evidence for tick-borne encephalitis virus in ticks in South Korea

First complete genomic characterization of two tick-borne encephalitis virus isolates obtained from wild rodents in South Korea

Complete genomic characterization of two tick-borne encephalitis viruses isolated from China

Genetic characteristics of the causative agent of tickborne encephalitis in Mongolia

Tickborne encephalitis virus

Isolation of TBE virus from the tick Ixodes hexagonus

System tick-infection agent and its emergent properties

Transmission of tick-borne encephalitis (TBE) virus by Dermacentor marginatus and D. reticulatus ticks

Ixodid ticks and the causative agent of tick-borne encephalitis. 2. The genera Dermacentor and Haemaphysalis

Replication of tick-borne encephalitis (TBE) virus in ticks Dermacentor marginatus

Isolation of the tick-borne encephalitis virus (TBE-virus) from the tick Haemaphysalis concinna Koch

Prevalence of tickborne Rickettsia and Ehrlichia in Ixodes persulcatus and Ixodes ovatus in Tokachi district, Eastern Hokkaido

Isolation of tick-borne encephalitis virus from Ixodes ovatus (Acari: Ixodidae) in Japan

Prevalence of tickborne encephalitis virus in ixodid ticks collected from the republic of Korea during 2011À2012

Contemporary epidemiology of infections with natural focality in Russia

Epidemiology and prophylaxis of tick-borne encephalitis. Tomsk

Tick-borne encephalitis: etiology, epidemiology and prophylaxis in Siberia. Novosibirsk: Nauka

Ixodidae ticks-parasites and vectors of infectious agents

The experimental transmission of the tick-borne encephalitis virus by ixodid ticks (the mechanisms, time periods, species and sex differences)

The present knowledge of tick-borne encephalitis vectors

Vertical transmission of tick-borne encephalitis virus between generations of adapted reservoir small rodents

Ecology of tick-borne encephalitis virus: part of Ixodidae tick males in its circulation

Sexual transmission of the tick-borne encephalitis virus in ixodid ticks (Ixodidae)

Experimental study of the role of male ixodid ticks in the circulation of the tick-borne encephalitis virus

Isolation of tick-borne encephalitis virus from Anopheles hyrcanus mosquitoes in Chuysky valley of Kyrgyzstan

Recurring isolation of virus belonging to tick-borne encephalitis group from blood-sucking mosquitoes in foreststeppe focies of Omsk hemorrhagic fever in Western Siberia

Malishevo strain of Negishi virus. Deposition sertificate of Russian State Collection of viruses N 682

To the question of the distribution of arboviruses in Priamurye and Sachalin

Arboviruses in Priamurye and Sachalin

International catalogue of arboviruses including certain other viruses of vertebrates

Experimental investigation of circulation of tick-borne encephalitis virus in the nest of bank vole at means of fleas Frontopsylla elata botis Jord., 1929. Reports of Irkutsk anti-plaque station

Experimental study of the role of fleas in the circulation of tick-borne encephalitis virus. Natural focies of the Far East. Khabarovsk

Arthropods of shelter complex in the natural focies of arboviral infections

Virological investigation of the role of blood-sucking arthropods belonging to shelter complex in the circulation of arboviruses

Efficient transmission of tick-borne encephalitis virus between cofeeding ticks

Isolation of tick-borne encephalitis virus complex from birds in Chukotka

Tick-borne encephalitis in children

Biological variants of the tick-borne encephalitis virus isolated in various foci of the disease

Zoning of the areal of tick-borne encephalitis. Moscow

Main features of tickborne encephalitis eco-epidemiology in Russia

Tick-borne encephalitis (TBE) trends in epidemiology and current and future management

A survey on cases of tick-borne encephalitis in European countries

Immunoprophylaxis of Tick-borne encephalitis

Calculation of the intensity of infection by Tick-borne encephalitis virus

Calculation of the intensity of the infection and morbidity of

Ecology of arboviruses

Prevention of tick-borne encephalitis at the present stage: strategy and tactics

Current aspects of the clinical picture of tick-borne encephalitis

Tick-borne encephalitis. Novosibirsk: Nauka

Persistent tick-borne encephalitis infection in man and monkeys: relation to chronic neurologic disease

Chronic tick-borne encephalitis. Novosibirsk: Nauka

Vaccination and tick-borne encephalitis, central

Tickborne encephalitis with fulminant course and lethal outcome in patients after plural vaccination

Prevention of tick-borne encephalitis by FSME-IMMUN vaccines: review of a clinical development programme

A nonadjuvanted whole-virus H1N1 pandemic vaccine is well tolerated and highly immunogenic in children and adolescents and induces substantial immunological memory

New strategy for specific prophylaxis of tick-borne encephalitis: an experience mass vaccination organization in Sverdlovsk region

Molecular epidemiology of Japanese encephalitis virus

Study on Japanese encephalitis virus. Animal experiments and mosquito transmission experiments

Japanese encephalitis

Genetic variation of Japanese encephalitis virus in nature

Genetic characterization of Japanese encephalitis virus genotype II strains isolated from 1951 to 1978

Origin and evolution of Japanese encephalitis virus in southeast Asia

Dogs as sentinels for human infection with Japanese encephalitis

Results of serological surveillance for Japanese encephalitis in 1980 in Primorsky krai

Circulation of arboviruses in contemporary ecological conditions of the Southern Far East. In: Lvov DK, editor. Arboviruses and arboviral infections

Migration of birds and the transfer of the infectious agents. Moscow: Nauka

Complex environmental and virological monitoring in the Primorje Territory in

An outbreak of Japanese encephalitis in the Torres Strait, Australia, 1995

Emerging viral diseases: an Australian perspective

Isolation of Japanese encephalitis virus from Culex annulirostris mosquitoes in Australia

Japanese encephalitis viruses from bats in Yunnan

Detection of Japanese encephalitis virus 2008-antibodies in bats in southern China

Importance of emergingÀreemerging infections for biosafety

The biological properties and variants of the Japanese encephalitis virus from a Russian collection

Past, present and future of Japanese encephalitis

Past, present and future of Japanese encephalitis

Ecology and geographical expansion of Japanese encephalitis virus

Molecular epidemiology of Japanese encephalitis in East Asia

Molecular epidemiology of Japanese encephalitis virus circulating in South Korea

Evidence of frequent introductions of Japanese encephalitis virus from South-East Asia and continental East Asia to Japan

Japanese encephalitis in mainland China

Japanese encephalitis virus genotype replacement

Introduction of Japanese encephalitis virus genotype I

Tissue culture inactivated vaccine for the prevention of Japanese encephalitis: experimental and laboratory process and control layout

Genetic analysis of Japanese encephalitis virus strains and variants from Russian collection

A highly attenuated host range-restricted vaccinia virus strain, NUVAC encoding the PRM, E, and NS1 agents of Japanese encephalitis virus prevent JEV viremia in swine

Handbook of Virology. Viruses and viral infection of human and animals

Japanese encephalitis vaccines-needs, flaws and achievements

Current use and development of vaccines for Japanese encephalitis

A strategic plan for Japanese encephalitis control by 2015

Single dose of Sa 14-14-2 vaccine provides long-tern protection against Japanese encephalitis; a case-control study in Nepal children 5 years after immunization

Natural foci infections on the Iona island in Okhotsk Sea

Natural virus foci in high latitudes of Eurasia

International catalogue of arboviruses and some others viruses of vertebrates

Virus taxonomy

Isolation of a group B arbovirus from Ixodes uriae collected on Three Arch Rocks national wildlife refuge

The role of parasites of swallow diggings in the preservation of natural foci infections

Phylogeny of TYU, SRE, and CFA virus: different evolutionary rates in the genus Flavivirus

International catalogue of arboviruses and some others viruses of vertebrates

Isolation of arboviruses from colonial seabirds of Barents Sea

An arbovirus cline across the northern hemisphere

Genetic characterization of tick-borne flaviviruses: new insights into evolution, pathogenetic determinants and taxonomy

Electron microscopic study of chicken fibroblasts infected with the Tyuleniy virus

The isolation of Meaban virus, a new Flavivirus from the seabird tick Ornithodoros (Alectorobius) maritimus in France

International catalogue of arboviruses and some others viruses of vertebrates

Concept of circumpolar distribution of arboviruses. In: Materials of 18-th Session of the Society of microbiologists, epidemiologists and parasitologists

Ecology of tick-borne viruses in colonies of birds in the USSR

Ixodes lividus Koch as the members of burrow-shelter complex. Studies of Fauna and Flora

Tiulenii antigenic group), isolated from Ixodes lividus ticks

Isolation of Tyuleniy virus from ticks Ixodes (Ceratixodes) putus Pick.-Camb. 1878 collected on Commodore Islands

Atlas of distribution of natural foci virus infections on the territory of Russian Federation. Moscow: SMC MPH RF Publ

Bloodsucking ticks (Ixodoidae)-vectors of disease of man and animals

Arboviruses isolated in the areas of the extreme North

Experimental infection of birds by Tyuleniy virus

Arboviruses of high latitudes in the USSR

Tick-borne viruses in western North America. I. Viruses isolated from Ixodes uriae in coastal Oregon in 1970

Migration of birds and the transfer of the infectious agents. Moscow: Nauka

Tyuleniy virus: possibly new arbovirus from group B

Arboviruses in high latitudes

Argas ticks (Argasidae)

Academy of Sciences of USSR;19774(4). Ixodoidea. Ixodinae subfamily ticks

Tuleniy virus. A new group B arbovirus isolated from Ixodes (Ceratixodes) putus Pick.-Camb. 1878 collected on Tuleniy Island, Sea of Okhotsk

Recent evolution of host-associated divergence in the seabird tick Ixodes uriae

International catalogue of arboviruses and some others viruses of vertebrates

The role of ecologo-virological zoning in prediction of the influence of climatic changes on arbovirus habitats

Isolation of arboviruses from Ixodes (Ceratixodes) putus Pick.-Camb. 1878 ticks collected in the bird colony on the Tyuleniy island, Okhotsk Sea

Arbovirus serological survey among marine and non-marine birds of Brittany

The isolation of Saumarez Reef virus, a new flavivirus, from bird ticks Ornithodoros capensis and Ixodes eudyptidis in Australia

Genetic characterization of viruses fromantigenic complex Tyuleniy (Flaviviridae, Flavivirus): Tyuleniy virus (TYUV) isolated from ectoparasites of colonial seabirds-Ixodes (Ceratixodes) uriae White, 1852 ticks collected in the hagh latitudes of Northern Eurasia-and Kama virus (KAMV) isolated from Ixodes lividus Roch, 1844 collected in the digging colonies of the middle part of Russian Plane

Dengue Virus (imported)

Travelrelated Dengue virus infection, the Netherlands

Antigenic relationships between flaviviruses as determined by cross-neutralization tests with polyclonal antisera

Dengue prevention and 35 years of vector control in Singapore

Dengue and US military operations from the SpanishÀAmerican war through today

Viremic degue virus infections in travelers: potencial for local outbreak in Northern Italy

Arbovirus circulation in the Republic of Guinea

Imported cases of arboviral infections in Russian Federation

New Dengue virus type 1 genotype in Colombo, Sri Lanka

Persistent emergence of Dengue

Problems of medical parasitology

Application of the Dengue virus NS1 antigen rapid test for on-site detection of imported Dengue cases at airports

Dengue and Dengue hemorrhagic fever, Brazil, 1981À2002

Modern status of the problem of Crimean hemorrhagic fever, West Nile fever and other arboviral infections in Russian Federation. Investigation of virus evolution in the limits of the problems of biosafety and socially significant problems. Materials of scientific conference

Modern status of laboratory diagnostics of denge fever (a review)

Dengue in patients with central nervous system manifestations

Sylvatic Dengue virus type 2 activity in humans

Co-infection with Chikungunya and Dengue virus in Delhi

Aedes aegypti L. and Aedes albopictus Skuse mosquitoes are a new biological threat to the south of Russia

Experimental investigations regarding the etiology of dengue fever

The future of dengue vaccines

Distribution of Aedes (Stegomyia) aegypti L. and Aedes (Stegomyia) albopictus Skus. mosquitoes on the Black Sea coast of the Caucasus

Production of immunity to denge with virus modified by propagation in mice

A clinical guide for early detection of Dengue fever and timing of investigations to detect patients likely to develop complications

Dengue 3 epidemic

Dengue virus infection in traveler returning from Groatia to Germany

The origin, emergence and evolutionary genetics of dengue virus

Phylogenetic relationships and differential selection pressures among genotypes of dengue-2 virus

Severe Dengue epidemics in Sri Lanka

First two autochtonous Dengue virus infections in metropolitan France

Viruses associated with epidemic hemorrhagic fevers of the Philippines and Thailand

Dengue virus type 3, Brazil

Unsuspected Dengue and acute febrile illness in rural and semi-urban southern Sri Lanka

Dengue in Greece in 1927 and 1928 and the pathogenesis of dengue hemorrhagic fever: new data and a different conclusion

Myanmar Dengue outbreak associated with displacement of serotypes 2, 3, and 4 by dengue 1

Dengue viremia titer and body response pattern, and virus serotype correlate with disease severity

Dengue and related arboviruses

Molecular evolution and epidemiology of dengue-3 viruses

Dengue/Dengue hemorrhagic fever: history and current status

Worlwide invasion of vector mosquitoes: present European distribution and challenges for Spain

Dengue/Dengue hemorrhagic fever: the emergence of a global health problem

Importation of Dengue virus type 3 to Japan from Tanzania and Cote d'Ivoire

Dengue guidelines for diagnosis, treatment, prevention and control

Bats as reservoir hosts for arboviruses

Ecological sounding of the USSR territory for natural foci of arboviruses

Studies on viruses in East African bats (Chiroptera). 1. Haemagglutination inhibition and circulation of arboviruses

About ecology of arboviruses, associated with shelter biocenosis. Progress in Science and Technics. Series {Virology. Arboviruses and arboviral infectionc, 24. Moscow: Russian Academy of Sciences

Ecological implications of antigenically related mammalian viruses for which arthropod vectors are unknown and avian associated soft tick viruses

Virus Taxonomy: Ninth Report of the International Committee on taxonomy of viruses

Results of virological survey of the vectors in Turkmenia

Studies of arthropod-borne virus infections in chiroptera. VI. Isolation of Japanese B encephalitis virus from naturally infected bats

Antigenic relationships of flaviviruses with undetermined arthropod-borne status

A new virus, Phnom-Penh bat virus, isolated in Cambodia from a shortnosed fruit bat

Monitoring of natural foci of arboviruses in Kyrgyzia

About ecology of Sokuluk virus

About relations between arboviruses, vectors and hosts. Progress in Science and Technics. Series {Virology. Arboviruses and arboviral infectionc, 24. Moscow: Russian Academy of Science

A new virus, {MMLc, enzootic in bats (Myotis lucifugus) of Montana

The Rio Bravo virus: virus identified with Group B arthropod-borne viruses by hemagglutination inhibition and complement fixation test

Characterization of viruses isolated from bats

Isolation at Dakar of a strain of arbovirus from the salivary glands of the bat (preliminary note)

Genetic characterization of Yokose virus, a flavivirus isolated from the bat in Japan

Arboviral zoonoses of Northern Eurasia (Eastern Europe and the Commonwealth of Independent States)

Natural foci of arboviruses in the USSR

Investigation of viruses, associated with the birds in Chuiskaya Valley in Kyrgyz SSR

Arbovirus infection in sub-tropic and in southern of tempered latitudes in USSR

Taxonomy of Sokuluk virus (SOKV) (Flaviviridae, Flavivirus, Entebbe bat virus group), isolated from bats (Vespertilio pipistrellus Schreber, 1774), ticks (Argasidae Koch, 1844), and birds in Kyrgyzstan

Foci of arboviruses in southern-western part of Osh district in Kyrgyz SSR

Virus of bats antigenically related to St. Louis encephalitis

Sokuluk" virus, a new group B arbovirus isolated from Vespertilio pipistrellus Schreber, 1775, bat in the Kirghiz SSR

About a vertebrate hosts of arboviruses in natural foci in Kirgizia

Studies on viruses in East African bats. (Chiroptera). 2. Virus isolation

International catalogue of arboviruses and some others viruses of vertebrates

Migration of birds and the transfer of the infectious agents. Moscow: Nauka

A neurotropic virus isolated from the blood of a native of Uganda

Isolation from human sera in Egypt of a virus apparently identical to West Nile virus

Handbook of Virology. Viruses and viral infection of human and animals. Moscow: MIA

Viral and rickettsial infections of man. Philadelphia

Complete genome sequences and phylogenetic analysis of West Nile virus strains isolated from the United States, Europe, and the Middle East

Pathogenecity of West Nile virus: molecular markers

Lineage 1 and 2 strains of encephalitic West Nile virus, central

West Nile and other zoonotic viruses as examples of emer-gingÀreemerging situations in Russia

West Nile virus isolates from India: evidence for a distinct genetic lineage

Putative new lineage of West Nile virus

West Nile fever

West Nile virus antibodies in wild birds

Fatal neurologic disease and abortion in Mare infected with lineage 1 West Nile virus

Lvov DK, Il'ichev VD. Migration of birds and the transfer of the infectious agents

Clinical characteristics of the West Nile fever outbreak, Israel

Surveillance for West Nile virus in dead wild birds, South Korea

Kunjin virus replicon-a novel viral vector

Molecular characterization and phylogenetic analysis of Murray Valley encephalitis virus and West Nile virus (Kunjin subtype) from an arbovirus disease outbreak in horses in Victoria

The changing epidemiology of Kunjin virus in Australia

Characterization of virulent West Nile virus Kunjin strain

First isolation of mosquito-borne West Nile virus in the Czech Republic

Mosquito (Diptera: Culicidae) surveillance for arboviruses in an area endemic for West Nile (Lineage Rabensburg) and Tahyna viruses in Central Europe

West Nile virus investigations in South Moravia

Usutu virus

Serologic survey of birds for West Nile Flavivirus in Southern Moravia (Czech Republic)

Serologic survey of potential vertebrate hosts for West Nile virus in Poland

Epidemiology and transmission dynamics of West Nile virus disease

Surveillance for West Nile, Dengue and Chikungunya virus infections

Genetic characterization of West Nile virus lineage 2

West Nile virus lineage 2 from blood donor

Assesing risk of West Nile virus infected mosquitoes from transatlantic aircraft implications for disease emergence in the United Kingdom

The molecular biology of West Nile virus: a new invader of the Western Hemisphere

West Nile virus in birds

Atlas of distribution of natural foci virus infections on the territory of Russian Federation. Moscow: SMC MPH RF Publ

West Nile virus epizootology

Neuroinvasive disease and West Nile virus infection

Early warning system for West Nile virus risk areas

Circulation of West Nile virus (Flaviviridae, Flavivirus) and some other arboviruses in the ecosystems of Volga delta, Volga-Akhtuba flood-lands and adjoining arid regions

Outbreak of West Nile virus infection in Greece

Surveillance for West Nile virus in American white pelicans

West Nile infection in killer whale

Evolution of new genotype of West Nile virus in North America

Arboviral zoonoses on Northern Eurasia (Eastern Europe and Commonwealth of Independent States

Ecologo-virological classification of arid landscapes on the territory of Kalmyk Republic

Investigation of virus evolution in the limits of the problems of biosafety and socially significant infections. Moscow

The experience of the supporting of field investigations in the natural foci of West Nile virus (Flaviviridae, Flavivirus) on the territory of Astrakhan region

West Nile fever among residents of the Astrakhan region in 2002

West Nile and other emergingÀreemerging viruses in Russia. Emerging biological threat. NATO science series. Series I. life and behavior sciences

Clinical profile and diagnostics algorithm of Crimean-Congo hemorrhagic fever and West Nile fever

Safety issues in new and emerging infections

Mosquito-and tick-transmitted infections in the Northern Part of Caspian Region

Population interactions between WNV and other arboviruses with artropod vectors, vertebrate animals and humans in the middle and low belts of Volga delta

The isolation of Dhori viruses (Orthomyxoviridae, Thogotovirus) and Crimean-Congo hemorrhagic fever virus (Bunyaviridae, Nairovirus) from the hare (Lepus europaeus) and its ticks Hyalomma marginatum in the middle zone of the Volga delta, Astrakhan region

Population interactions of West Nile virus (Flaviviridae, Flavivirus) with arthropod vectors, vertebrates, humans in the middle and low belts of Volga delta in

Arbovirus infections in ecosystems of Volga-Akhtuba and Volga delta high zone. III Conference of Russian scientists with foreign participation "Fundamental sciences and progress in clinical medicine

Ecological and physiological peculiarities of Ixodidae ticks Rhipicephalus pumilio Sch., 1935 on the territory of north-western part of Caspian region. In: Modern problems of epizootology

Circulation of West Nile virus (Flaviviridae, Flavivirus) among wild animal populations on the territory of North-Western Caspian Region

Distribution of some arboviruses on the territory of Kalmyk Republic according to investigation of human and domestic animal blood sera (2001À2002 data)

The role of ecologo-virological zoning in prediction of the influence of climatic changes on arbovirus habitats

Role of paleogeographical reconstruction in the prognosis of arbovirus natural habitats

Novosibirsk: CERIS

Isolation of two strains of West Nile virus during an outbreak in southern Russia

Virus taxonomy. 9th Rep Intern Comm Taxonomy of Viruses

Taxonomic structure of Orthomyxoviridae: current

TAXONOMY AND ECOLOGY views and immediate prospects

An overlapping protein-coding region in influenza A virus segment 3 modulates the host response

Identification of novel influenza A virus proteins translated from PA mRNA

Genotypic structure of the genus influenza A virus

New world bats harbor diverse influenza A viruses

A complicated message: identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA

A distinct lineage of influenza A virus from bats

New subtype of influenza A virus from bats and new tasks for ecologo-virological monitoring

Influenza A Viruses (H1ÀH18)

John Locke and the preface to Thomas Sydenham's Observationes medicae

Microorganisms, toxins, and epidemics. Moscow

History of mass diseases

Evolution of highly pathogenic avian influenza virus (H5N1) in ecosystems of Northern Eurasia

Influenza: the last great plague. An unfinished story of discovery

Surveillance for pandemic influenza

Pandemic influenza 1700À1900, a study of historical epidemiology

Spanish" flu (1918À1920) in the context of other influenza pandemic and "avian flu

Doctrine of epidemic diseases. Tomsk; 1935

Swine influenza: III. Filtration experiments and etiology

The incidence of neutralizing antibodies for swine influenza virus in the sera of human beings of different ages

Experiments on the immunization of ferrets and mice

A virus obtained from influenza patients

Afanasiev, the founder of St. Petersburg microbiological school

Vorläufige Mittheilungen ü ber den Erreger der Influenza

Die Aetiologie der Influenza

Clinically significant agents of respiratory infections. Conspectus for clinical physician

Leningrad: Nauka

Symposium on the Asian influenza epidemic

A history of Influenza

Influenza and its prophylaxis

Kiev: Zdorovie

Molecular ecology of influenza and other emerging viruses in Northern Eurasia: global consequences

Spread of new pandemic influenza A(H1N1)v virus in Russia

Influenza provoked by new pandemic virus A/H1N1 swl: clinics, diagnostics, treatment. Methodological recommendations. Moscow

Trends in the spread of pandemic influenza A(H1N1) swl in the Far East in 2009

Evolution of emerging influenza viruses in Northern Eurasia

Historical perspectiveemergence of Influenza A (H1N1) viruses

Returning of Influenza A-prim and the problem of pandemic strains emergence

Animal flu (of mammals and birds)

Diseases of the birds

Zentralblatt fü r Bakteriologie-100 years ago an outbreak of fowl plague in Tyrol in 1901

Eugenio Centanni and the rise of immunology in Italy

Epizoozia tifoide nei gallinacei

Sero-immunologic studies on incomplete forms of the virus of classical fowl plague

Vergleichende sero-immunologische Untersuchungen ü ber die Viren der Influenza und klassischen Geflü gelpest

The isolation and classification of Tern virus: influenza A-Tern South Africa-1961

Possible significance of natural biocenoses in the variability of influenza A viruses

Ecology of influenza viruses in lower mammals and birds

Influenza A viruses-a sum of populations with a common protected gene pool

Virology reviews, 2. Glasgow: Bell and Bain Ltd

Populational interactions in biological system: influenza virus A-wild and domestic animalshumans; relations and consequences of introduction of high pathogenic influenza virus A/H5N1 on Russian territory

Avian influenza in Northern Eurasia

Hemagglutination reaction in infectious sinusitis of ducklings

Virus influenza of ducklings

Virus influenza of ducks. Poultry diseases. Moscow: Kolos

Biological properties of animal influenza viruses

Influenza in the USSR: new antigenic variant A2/Hong Kong/1/68 and its possible precursors

A new variant of influenza A2 (Hong Kong) 1À68 virus and its connection with the outbreaks of influenza observed in the USSR in 1968

Study of some biological properties of influenza virus strains of poultry and horses isolated in the USSR

Antigenic characteristics of the influenza viruses isolated from domestic animals and birds in the USSR

Some observations on the circulation of influenzaviruses in domestic and wild birds

A new variety of chicken influenza virus

Migration of birds and the transfer of the infectious agents. Moscow: Nauka

Isolation of the Hong Kong variant of type A influenza virus from sick chickens in the Kamchatka region

Serological evidence of the circulation of various variants of the influenza type A viruses among migratory birds in northern and western zones of the USSR

Properties of Hav6Neq2 and Hsw1(H0)Nav2 influenza viruses isolated from waterfowl in southern Turkmenia

Influenza viruses isolated from wild birds

Persistence of the genes of epidemic influenza viruses (H1N1) in natural populations

Influenza virus A/Anas Acuta/Primorie/695/76 isolated from wild ducks in the USSR

Comprehensive study of the ecology of the influenza viruses in Komandory Islands

Isolation of an influenza virus, similar to A/Port Chalmers/1/73 (H3N2) from a common murre at Sakhalin Island in USSR (strain A/common murre/Sakhalin/1/74)

Influenza virus A/Anas acuta/Primorie/730/76(H3N2) isolated from wild ducks in the Maritime Territory

Isolation of influenza strains identical to influenza virus A/Anglia/42/72 from semisynanthropic bird species in Rovno Province, the Ukrainian SSR

Human and avian viruses of the Hong Kong series

Isolation of an influenza virus from a tree sparrow and the infection rate of the virus in wild birds in the mid-Dnieper Region

A new avian influenza virus from feral birds in the USSR: recombination in nature?

Isolation of influenza A viruses from wild migratory waterfowl in the north of Europian part of the USSR

Incidence of influenza virus infection in black-headed gulls

Isolation of influenza virus with the antigenic formula Hav4 Nav2 and Hav5 Nav2 during epizootic infection among sea gulls in the Astrakhan district in the summer of 1976

Isolation of influenza virus from Chlidonias nigra and serologic examination of the birds for antibodies to influenza virus

Ecology and evolution of influenza viruses in Russia (1979À2002)

Antigenic and genetic characterization of a novel hemagglutinin subtype of influenza A viruses from gulls

Circulation of the influenza A virus of H13 serosubtype among seagulls in the Northern Caspian

Antigenic and molecular characterization of subtype H13 hemagglutinin of influenza virus

Monitoring of the circulation of influenza A viruses in the populations of wild birds of the North Caspian

Isolation of influenza virus A (Orthomyxoviridae, Influenza A virus), Dhori virus (Orthomyxoviridae, Thogotovirus), and Newcastle's disease virus (Paramyxoviridae, Avulavirus) on the Malyi Zhemchuzhnyi Island in the north-western area of the Caspian Sea

Molecular characterization of a new hemagglutinin, subtype H14, of influenza A virus

Precursor genes of future pandemic influenza viruses are perpetuated in ducks nesting in Siberia

Highly pathogenic Influenza A (H5N1) virus: epidemic threat is remaining. Infectious diseases and antivirals. Materials of X-th scientific-practice conference

Isolation of influenza A viruses from wild birds and a muskrat in the western part of the East Asia migration route

Evolution of H4, H5 influenza A viruses in natural ecosystems in Northern Eurasia

Options for the control of influenza V. International congress series

Genetic diversity of influenza A virus in the populations of wild birds in the south of Western Siberia

The 2003 results of monitoring of influenza A virus in the populations of wild birds in the south of Western Siberia

The study of circulation of influenza and West Nile viruses in the natural biocenoses of Mongolia

Medical virology. Moscow: Guide. Medical information agency

Postreassortment changes in influenza A virus hemagglutinin restoring HA-NA functional match

Intergenic HA-NA interactions in influenza A virus: postreassortment substitutions of charged amino acid in the hemagglutinin of different subtypes

Evidence of influenza A virus RNA in Siberian lake ice

Isolation of influenza A/H5N1 virus strains from poultry and wild birds in West Siberia during epizooty

Clinical symptoms of bird disease provoked by highly pathogenic variants of influenza A/H5N1 virus in the epicenter of epizooty on the south of Western Siberia

Molecular genetic analysis of the biological properties of highly pathogenic influenza A/H5N1 virus strains isolated from wild birds and poultry during epizooty in Western Siberia

Avian flu: H5N1 virus outbreak in migratory waterfowl

H5N1 influenza virus, domestic birds

Study of highly pathogenic H5N1 influenza virus isolated from sick and dead birds in Western Siberia

Avian Influenza A virus (H5N1) outbreaks. Kuwait, 20

Summary of avian influenza activity in Europe

Highly pathogenic avian influenza virus subtype H5N1 in Africa: a comprehensive phylogenetic analysis and molecular characterization of isolates

Confirmation of H5N1 avian influenza in Africa

attitudes, and practices regarding avian influenza (H5N1)

Highly pathogenic influenza A/H5N1virus-caused epizooty among mute swans (Cygnus olor) in the low estuary of the Volga River

Outbreak of avian influenza virus H5N1 in India

Isolation of highly pathogenic avian influenza (HPAI)

) and their incorporation to the Russian Federation State Collection of viruses

Molecular genetic characteristics of the strain A/chicken/Moscow/2/2007 (H5N1) strain from a epizootic focus of highly pathogenic influenza A among agricultural birds in the near-Moscow region

Epizooty caused by high-virulent influenza virus A/ H5N1 of genotype 2.2 (Qinghai-Siberian) among wild and domestic birds on the paths of fall migrations to the north-eastern part of the Azov Sea basin (Krasnodar Territory)

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