key: cord-0926582-gmkh0pxr authors: Kiselev, O. I.; Vasin, A. V.; Shevyryova, M. P.; Deeva, E. G.; Sivak, K. V.; Egorov, V. V.; Tsvetkov, V. B.; Egorov, A. Yu.; Romanovskaya-Romanko, E. A.; Stepanova, L. A.; Komissarov, A. B.; Tsybalova, L. M.; Ignatjev, G. M. title: Ebola hemorrhagic fever: Properties of the pathogen and development of vaccines and chemotherapeutic agents date: 2015-08-14 journal: Mol Biol DOI: 10.1134/s002689331504007x sha: f536d6edc41c842d17f0add8483ee891d76bddb7 doc_id: 926582 cord_uid: gmkh0pxr Ebola hemorrhagic fever (EHF) epidemic currently ongoing in West Africa is not the first among numerous epidemics in the continent. Yet it seems to be the worst EHF epidemic outbreak caused by Ebola virus Zaire since 1976 as regards its extremely large scale and rapid spread in the population. Experiments to study the agent have continued for more than 20 years. The EHF virus has a relatively simple genome with seven genes and additional reading frame resulting from RNA editing. While being of a relatively low genetic capacity, the virus can be ranked as a standard for pathogenicity with the ability to evade the host immune response in uttermost perfection. The EHF virus has similarities with retroviruses, but belongs to (–)RNA viruses of a nonretroviral origin. Genetic elements of the virus, NIRV, were detected in animal and human genomes. EHF virus glycoprotein (GP) is a class I fusion protein and shows more similarities than distinctions in tertiary structure with SIV and HIV gp41 proteins and even influenza virus hemagglutinin. EHF is an unusual infectious disease, and studying the molecular basis of its pathogenesis may contribute to new findings in therapy of severe conditions leading to a fatal outcome. The first recorded outbreak of Ebola hemorrhagic fever (EHF) occurred in October 1976 in the Demo cratic Republic of Congo [1] . The outbreak of 2013-2014 is thought to share many features with the out break of 1976 [2] , both being caused by the Zaire Ebola virus and starting in rural forested areas where hunting for bush meat is common [1] . Patients were admitted to regional hospitals in grave conditions with symptoms resembling malaria, typhoid fever, Lassa fever, yellow fever, or influenza [2, 3] The epidemics was a severe challenge for the health care systems of West African countries, and the total ill preparedness of the community caused panic and social upheaval, requiring military units to bring the affected territories under control. Yet the most important lessons learned from the current situation with EHF are that health care systems are not prepared for such outbreaks in virtually all countries, vaccines are difficult to develop, and highly effective broad spectrum antiviral chemo therapy agents are unavailable. AND OUTBREAK OF 2013-2014 The virus Zaire ebolavirus is a causal agent of the EHF outbreak in West Africa. The Ebola virus was first identified in 1976 and caused sporadic EHF outbreaks with a high mortality in Africa, being assigned conse quently to group A pathogens, which are potential bio terrorism agents [1, 4] . In terms of general virology, the Ebola virus is currently a reference standard of pathogenicity, and its studies are of basic importance for solving the most complex problems in treating and preventing virus infections. The species Zaire ebolavirus is the most pathogenic species of the genus Ebolavirus (family Filoviridae, order Mononegavirales). The family Filoviridae Infection with Reston ebolavirus is asymptomatic, while the other four species are highly pathogenic for humans [1] [2] [3] [4] [5] . The taxonomy of the genus Ebolavirus has been considered in a special article published in Viruses [6] by a team including Russian researchers who contributed substantially to studying the problem both in Russia and abroad. A current classification of the genus Ebolavirus is shown in Fig. 1 . The Ebola virus is found in primates, field mice, and bats. In bats, infection does not lead to a disease outbreak and is virtually asymptomatic. The fact sug gests that bats, in particular, fruit bats of the family Pteropodidae, are a natural reservoir and intermediate host of the Ebola virus [7] . A genetic analysis of Ebola virus isolates showed that the current outbreak started with virus transmission from the straw colored fruit bat Eidolon helvum to humans [2] . It should be noted that a greater range of intermediate hosts is possible for the virus. It is of interest that viruses of the family Filoviridae belong to a limited group of viruses, known as the non retroviral integrated RNA viruses (NIRVs), whose specific elements were identified in animal genomes [8] . A high structural similarity was observed for the receptor protein GP of the Ebola virus with the Env proteins of endogenous retroviruses and placental syn cytins of humans [9] . Common elements of the Ebola virus and retrovirus are of principal importance for understanding the key factors of the Ebola virus pathogenicity [10, 11] . A high similarity was addition ally detected between Ebola virus GP and well known influenza virus hemagglutinin, facilitating a better understanding of the GP tertiary structure and inhibi tor design [12, 13] . A team of WHO epidemiologists identified the Ebola virus as a causal agent of the hemorrhagic fever outbreak that occurred in the Ebola River valley (Zaire, Central Africa) in 1976 [1] [2] [3] . A total of 23 EHF outbreaks were registered since that time. The outbreak of 2014 started in Guinea (West Africa) and spread to Liberia, Sierra Leone, and Nigeria. A phylo genetic analysis of Ebola virus genomic sequences gives grounds to think that the virus strain responsible for the 2014 outbreak relatively recently found its way from Central to West Africa [2, 3] . A phylogenetic analysis confirmed genetic similar ity between Ebola virus lineages involved in the three last EHF outbreaks. The finding suggests a common ancestor for the viruses involved and supports the hypothesis that each EHF outbreak was caused by independent transmission of the virus from one genet ically diverse population [2] . The genetic similarity and close phylogenetic relationship of the genomes of 2014 Ebola viruses indicate that a single act of trans mission from a natural reservoir was followed by stable transmission of infection among humans, leading to an epidemic outbreak. This epidemiological situation basically differs, for instance, from epidemics of avian flu, which was characterized by multiple focal out breaks in endemic regions and a low transmission rate among humans. Hence, Ebola virus infection seems to be extremely contagious. There are estimates that a single event of crossing the species barrier would be enough for the virus to spread rapidly in the popula tion [2] . The EHF outbreak starting in December 2013 involved mostly Guinea, Liberia, Senegal, Sierra Leone, and Nigeria among African countries [14] [15] [16] . Cases observed in the United States and European countries occurred in healthcare workers and mission aries. Estimates published in mass media for the risk of EHF being transferred to other countries, including Russia, are based on the passenger traffic statistics and The epidemiological situation as of late October 2014 and a forecast for a subsequent period (early 2015) are shown in Fig. 2 [14, 15] . The predicted num bers of cases of and deaths from Ebola change rapidly; the number of deaths may reach one million people in the nearest future according to some estimates. Mod erate forecasts estimate the number of cases in the pri mary foci of the EHR outbreak at several tens of thou sands of people. As of October 25, 2014, the Ebola morbidity rate ceased to grow in Nigeria. This is an early sign that the spread of infection can be controlled using anti epidemic measures [15] . The Ebola virus is a (-)RNA virus; i.e., its repro duction depends on its own polymerase complex. The Ebola virus genome is a single stranded (-)RNA of approximately 19000 nt [19] . Seven open reading frames identified in the genome code for major virus proteins and occur in the following order: 3' NP VP35 VP40 GP/sGP VP30 VP24 L 5' (Fig. 3) . The genes are separated by short untranslated sequences [2, 13, 18] . The leader and trailer regions are not transcribed, harboring control signals for transcription, replica tion, and genomic RNA packaging in virus particles [18] . Functions of the virus proteins are summarized in Table 1 . The Ebola virus genes each code for one protein [13, 18] . The only exception is GP, which produces not only the main translation product GP, but also sGP, resulting from transcriptional RNA editing [13, 17, 18] . The 300 first amino acid residues of sGP are the same as in the N terminal region of GP, but the C terminal sequence of sGP is unique [18, 19] . Infected cells secrete sGP as a homodimer stabilized by disulfide bonds. sGP is an important component of the system that helps the Ebola virus to evade the immune response; its content in the peripheral blood increases in the course of infection. Shortened sGP (ssGP) was identified recently [13, [17] [18] [19] . Among all Ebola virus proteins, GP was studied most comprehensively (Fig. 3) , and its spatial struc ture is known [17, 18] . GP attracts particular interest because it executes the most important function in the virus life cycle, interacting with a cell receptor and ensuring virus fusion with the membrane [18] . Cell infection starts with GP binding with the TIM 1 cell protein, which belongs to a class of receptors that pos sess T cell immunoglobulin like and mucin like domains [20] . TIM family proteins play a key role in regulating the cell immune response to virus infection. The TIM 1 receptor is involved in the allergic response and the pathogenesis of asthma [20] . The Ebola virus enters cells via clathrin mediated endocy tosis or receptor mediated macropinocytosis [19] [20] [21] . The interaction of GP1 with the Niemann-Pick C1 cholesterol transporter (NPC1) was also found to play a role in virus entry into the cell at the late endosome stage [17] . In acidosis, highly glycosylated at the mucin like domain, nonprocessed GP is cleaved in endosomes into GP1 and GP2 by cellular furin and the cysteine proteases CatL and CatB [21] . Proteolysis occurs during sGP formation as well. GP proteolytic processing leads to conformational changes in the GP2 trimer, which initiates fusion of the endosomal and virus membranes to release the virus nucleocapsid into the cytoplasm. It should be noted that GP con tains virus neutralizing antibody determinants and is consequently most often used to design anti EHF vac cines [17, 21] . Protection from the host immune system involves several Ebola virus proteins (Table 1 ). In particular, VP35 and VP24 suppress innate immunity; VP35 inhibits interferon production; and VP24 prevents the transport of phosphorylated STAT1 into the nucleus, thus suppressing the interferon mediated antivirus response [13, 17, [22] [23] [24] . There are many molecular targets of the Ebola virus among components of the host immune system. Their list can be extended to all levels of body protection from virus infections [22] . In general, the Ebola virus acts as the most potent immu nosuppressive agent that causes immunoparalysis, rendering the organism incapable of recognizing virus antigens [10, 11, 24] . With a rapid development of infection, the multilevel immunosuppressive system prevents the body from producing an adequate immune response. This circumstance is to a great extent responsible for numerous deaths from EHF, which occurs as early as 9-12 days of disease. Other severe conditions include systemic organ failure, hem orrhagic pulmonary edema, sepsis, and disseminated intravascular coagulation (DIC) [25, 26] . HEMORRHAGIC FEVER The EHF development includes the following stages: an incubation period, an early symptomatic stage, a late symptomatic stage, and a terminal or recov ery period [16, 27] . Another classification in broad use is based on the consequent development of signs and symptoms of vital organ involvement (Table 2 ). In total, the main clinical signs and symptoms of EHF resemble sepsis [25, 27] . The clinical status of EHF patients is characterized by systemic virus repli cation (high level viremia), cytokine storm, general immune suppression resembling immunoparalysis, septic condition (an impaired function of the intesti nal and vascular epithelia), impaired coagulation, tis sue edema, and increased total vascular permeability. Patients die of multiple organ failure, acute respiratory distress, or coagulopathy [14, 16, 17] . The develop ment of the infection process caused by the Ebola virus and the main components of its pathogenesis are shown in Fig. 4 . The Ebola virus infects immune cells [16, 28] . The most important consequences of infection are leuko penia, dissemination of virus infection in the body, and suppressed presentation of virus antigens by antigen presenting cells (dysfunction and apoptosis of dendrite cells) [28] . Infection of endothelial cells alters the bar rier function of the vascular endothelium and leads to hypovolemic shock and hemorrhagic tissue edema. Activation of tissue factors (plasminogen) leads to fatal coagulopathy. The immune response is sup pressed at many levels, which is related primarily to the effect of the immunosuppressive domain of GP [10, 11] . Cytokine storm is an overproduction of pro inflam matory cytokines, which cause a systemic inflamma tion syndrome with a diffuse inflammatory reaction of tissues and blood vessels. The EHF sequels develop in the presence of a cytokine storm and immunoparalisis due to infection of macrophages and dendrite cells and [22, 23] soon after a discovery of virus proteins acting as interferon antagonists [29] . As a result, VP35 was identified as a protein that to blocks interferon pro duction in early infection [22, 23] . VP35 is generally thought to play a crucial role in the pathogenesis of EHF, contributing to the suppression of antivirus cell defense. Oxidative stress. Endothelial cell infection and induced synthesis of enzymes that cause oxidative stress and mass apoptosis are of utmost importance for the pathogenesis of Ebola virus infection [26, 30, 31] . Infection of endothelial cells alters their intercellular contacts and the association with the intima (vascular basement membrane) of vessels. NO synthase expres sion is simultaneously induced in endothelial cells, resulting in NO overproduction [26] and nitrosative stress caused by peroxynitrite and other reactive oxy gen species. A higher NO level in the peripheral blood correlates with the disease severity and high mortality [26, 30] . Erythrocyte hemolysis in tissues affected by hemorrhagic edema leads to the most destructive gen eration of reactive oxygen species, especially in the lungs [16, 32, 33] . Endothelial dysfunction and mass endotheliocyte apoptosis. Virus particle budding in lipid rafts of endothelial cells is thought to destabilize the vascular wall and thereby cause bleedings and hemorrhages. A direct effect of virus proteins on the endothelial barrier integrity cannon also be excluded [31] [32] [33] [34] [35] . A no less destructive effect is exerted by the tumor necrosis fac tor (TNF) as a leading component of the cytokine storm [25] [26] [27] . It should be noted that defects in the endothelial barrier arise primarily because cell con tacts between endotheliocytes are structurally impaired [17, 26, 28, 31, [33] [34] [35] . Hence, therapy should be aimed at restoring the integrity of the endot helial barrier and protecting the endothelium from cytokine storm components [35] [36] [37] [38] [39] [40] [41] [42] . A destructive effect of infection on the vascular endothelium and macroph age activation (Fig. 4) lead to disruption of intercellu lar contacts, causing endothelial dysfunction and con sequent hemorrhagic tissue edema. Blood clotting accompanies hemorrhagies [17, 26, 28, 31, [33] [34] [35] . Activation of the tissue plasminogen activator devel ops as an inadequate compensatory reaction [31, [33] [34] [35] , inevitably stimulating the coagulation cascade (Fig. 4) . Disseminated intravascular clotting (DIC) is the most severe consequence of the process. The risk of DIC is substantially reduced by the use of activated pro tein C drugs (Xigris) [40, 41] . Treatment with recombi nant nematode anticoagulation protein c2 (rNAPc2) was found to protect up to 33% of primates from fatal Ebola virus infection [42] . Large scale generation of immune complexes in circulation is also considered to be a factor that provokes blood clotting [28, [43] [44] [45] . The disease outcome is usually determined on days 6-11, when either the acute phase crisis resolves or a transition to the terminal stage occurs [14, 29, [31] [32] [33] [34] [35] [36] [37] [38] [39] . This circumstance shows that the therapy window is limited and that a medical decision is to be made within a short while; it is therefore of immense impor tance to detect the turning period [25, [40] [41] [42] 46] . The interaction of the Ebola virus with immune and other cells is illustrated in Fig. 4 . The virus initially interacts with immune cells to cause the following alterations: NK cell apoptosis, cooperative lympho cyte apoptosis, dendrite cell infection, and macroph age activation with oxidative stress, which is associated with overproduction of reactive oxygen species. Immunosuppression targeting NK and T cells is an important effect of infection [10, 11] . GP and the interferon antagonists VP35 and VP24 were identified as immunosuppressive virus proteins [22, 30, 47] . Higher pathogenicity of the Ebola virus compared with the Marburg virus is due to sGP synthesis [17, 24] . Antigenic subversion due to secretion of sGP as a trun cated GP form [24] leads to antibody neutralization in circulation, thereby substantially reducing the immune response to infection. Thus, the Ebola virus targets various elements of the host immune system, such as monocytes, macrophages, and dendrite cells. Multiple organ failure is caused by infection and mass apoptosis of vascular and lung endothelial cells. Anti body dependent enhancement (ADE) of the infection process is another mechanism involved in both stimu lating the virus infection and facilitating host immu nity evasion [39, 43, 44] . The virus capability of ADE should be considered when constructing vaccines [24, [43] [44] [45] . It is known also that the Ebola virus interacts with complement components and cell Fc receptors to promote a spreading of infection among immune cells and various organs and tissues [22, 43] . A diagnostic monitoring is essential when a new infection arises or a known one recurs. Rapid labora tory diagnosis is one of the main prerequisites to a reli able infection control, timely identification of infected individuals, quarantine activities, and, most impor tant, timely medical decisions in administering effec tive treatment in a timely manner. The main tests employed in laboratory diagnosis of EHF are summa rized in Table 3 . A RT PCR test (Central Institute of Epidemiology, Russian Federal Service for Surveil lance in Consumer Right Protection and Human Well being) is currently approved in the Russian Fed eration. Simple rapid tests are essential for diagnosis in the primary foci of infection [46, 47] . Rapid progress was seen again in developing rapid diagnostic tests on the basis of biochips, immunochromatographic strips, and various modifications of ELISA [46] [47] [48] . New approaches were proposed in several Russian projects. PRACTICAL REQUIREMENTS AND PRIORITY OF ANTIVIRUS DRUGS Only limited agents effective in EHF are available for obvious reasons. Hence, the WHO had to intervene in the drug approval system and to support the vac cines and antivirus drugs that had been studied most comprehensively and tested in primates. A general opinion is that monotherapy is not promising in EHF [3, 4, 25, 28] . A combination of medications with intensive care is the only means to achieve a desirable effect [25, 28] . The efficacy of this approach can be illustrated with the case of a WHO epidemiologist who worked for a long time in an EHF focus of Sierra Leone. When first signs of the disease appeared, the patient was treated according to a protocol accepted in malaria [25] . EHF was then diagnosed by a PCR test, and transfusions, ciprofloxacin, and metronidazole were administered [25] . On day 10 of illness, the patient was airlifted to Hamburg. He was admitted to an intensive care unit in a grave condition; therapy was aimed primarily at treating sepsis. The patient recov ered and was discharged from the hospital on day 26. It should be noted that the patient did not receive anti viral drugs or the ZMapp cocktail. A conclusion was made that severe EHF cases can be treated success fully with conventional intensive care measures [25] . Thus, the availability of adequate intensive care and modern treatments for sepsis underlies successive therapy for EHF [25, 46] . However, it should be noted that the development of chemotherapeutics in modern pharmacology is focused to a great extent on commercial success and excess profits, as is evident from the fact that designing and testing antiviral drugs to inhibit Ebolavirus repli cation is of no interest to the majority of pharmaceuti cal companies worldwide and especially in Russia. It would be surprising indeed if Anaferon, Ingavirin, Kagotsel, and many other Russian drugs were pro posed for treating highly dangerous infections, such as EHF. The main drugs used to prevent and treat EHF are summarized in Table 4 . Vaccines. It is clear that the primary task is to develop disease preventing vaccines to ensure safety of healthcare workers and to perform large scale vacci nation in the endemic regions of West Africa for erad icating EHF. Attempts were also made to develop vac cines and vaccination protocols aimed at urgent dis ease prevention in contacting persons during the incubation period [51] [52] [53] [54] [55] [56] 63] . More than ten vac cines are currently being developed and evaluated in clinical studies. Recombinant technologies are employed as a basis in constructing vaccines against the Ebola virus [52] . Recombinant vaccines are many and include those based on the vaccinia virus, Venezu elan equine encephalitis virus, type 3 parainfluenza virus, and several other common vectors. The WHO supported vesicular stomatitis virus and chimpanzee adenovirus (ChiAd3) based vaccines expressing Ebola virus antigens [56, 64] . An Ad5 based vaccine was not considered to be promising because anti adenovirus immunity is widespread in the popu lation. A main drawback is that usual cold chain logis tics is insufficient with all vaccines, which should be stored at extremely low temperatures (at liquid nitro gen temperatures in some cases). Such storage is prob lematic in African countries, rendering mass vaccina tion difficult and expensive. Humanized antibodies. The ZMapp cocktail of humanized monoclonal antibodies neutralizes infec tion activity of the Ebola virus in the blood and tissues [57, 58] and occupies a special place among the bio Therapeutic efficacy verified in one patient [35, 49] logics listed in Table 4 . It took at least 15 years of basic research to develop the drug. A technological implemen tation of the project is worthy of being among the best achievements of the 21st century [57] and is a source of pride for the Ministry of Health of Canada [58] . Pathogenesis based drugs are aimed at controlling and managing the infection process to prevent dys function of vital organs and its sequels, including fatal outcomes. The drugs actually target the causes of fatal outcomes. In their initial studies, researchers of the Vector State Research Center of Virology and Biotechnology were the first to try to design drugs that would correct the development of irreversible changes in affected tis sues [32] . The unique drug Desferal was proposed to protect the lungs from hemorrhagic edema and conse quent heme induced oxidative stress [32] . Anti TNFα antibodies were used for the first time to reduce the damaging effect of the cytokine storm [36] . A fibrin derived peptide (a domain E1 fragment). Therapeutic use of peptide Bβ 15-42, which is known as FX06 and interacts with VE cadherin, is of special interest. The peptide results from plasmin catalyzed proteolysis of fibrin. Therapeutic efficacy of the pep tide FX06 was studied in animals with myocardial rep erfusion injury, which provides a model of myocardial infarction [35] . FX06 was shown to prevent an increase in vascular permeability in lipopolysaccharide induced septic shock models. FX06 displayed good therapeutic properties in preventing the increased vascular perme ability syndrome in models with dengue virus induced shock. Studies of the mechanism of action showed that the peptide FX06 prevents stress induced activation of the RhoA kinase [35] . It should be noted that FX06 has a high proline content (GHRPLDKKREEAPSLRPA PPPISGGGYR), suggesting a regulatory function towards PDZ binding domains. Based on preclinical findings, FX06 was used to treat an EHF patient from Sierra Leone in Hamburg [25, 49] . Therapeutic suc cess was attributed directly to the use of FX06 in this case [35, 49] . Apart from the above medicines, there are antiviral drugs based on small interfering RNAs or modified antisense oligonucleotides, combining certain advan tages with considerable drawbacks [27, 28, 49, 55, [59] [60] [61] [62] 64] . Recommendations for treating EHF patients with due regard to the new data on EHF pathogenesis and the causes of fatal outcomes were developed at the Institute of Influenza [46] . OF EBOLA VIRUS REPLICATION Antiviral therapy with broad spectrum chemother apeutics is a priority of special significance according to the WHO. Because high level viremia accompanies EHF and the viral load correlates with the clinical course of the disease, etiotropic therapy aimed at sup pressing virus replication is of utmost importance. [65] . (d) Ade nosine analog BCX 4430 [66] . (e) T 705 (pyrazine carboxamide), which inhibits viral RNA dependent RNA polymerase [67] [68] [69] . (b) Estrogen receptor inhibitor clomiphene, which suppresses the endosomal stage of infection [70, 71] . (c) Adenosine A2b receptor antagonist ZM241385 [74] . Great interest is attracted by the small molecules (low molecular weight compounds) that were tested in pre clinical or Phase I clinical studies and showed efficacy in EHF. The set includes brincidofovir (CMX001), favipiravir (T 705), umifenovir, BCX 4430, FGI 103, triazavirine, ZM241385, and new triazolo purine and triazolo pyrimidine derivatives (Fig. 5) . BCX 4430, FGI 103, T 705 [25, 28, 49, [64] [65] [66] [67] [68] [69] [70] [71] , and triazavirine [72, 73] are considered to be the most promising. Tri azavirine is a triazolo triazine drug with broad spec trum activity towards hemorrhagic fever viruses [73] , although reference studies are necessary for testing its efficacy against the Ebola virus. Adenosine receptor modulators and Toll like receptor blockers were found to provide for a better survival of laboratory animals with sepsis accompa nied by multiple organ failure [74] . New approaches help to substantially augment the set of drugs effective in EHF and other dangerous human diseases. A mass screening reveals substances with unexpected proper ties even among approved drugs [70, 71] , and such drugs actually require only EHF to be approved as a new indication. A new mechanism of action was described for umifenovir (Arbidol), which conse quently can be improved to serve as an Ebola virus rep lication inhibitor [75] . Studies at the Institute of Influ enza made it possible to complete the design of antivi ral agents of the series and to expand the activity spectrum of new compounds. New information on the development of drugs and vaccines against the Ebola virus is available at many web sites, including those of the WHO, CDC, and Institute of Influenza. Ebola virus disease in West Africa: The first 9 months of the epidemic and forward projections Outbreak of Ebola virus disease in Guinea: Where ecology meets economy Bioterrorism: A national and global threat Immune response to Filovirus infections Ebola virus antibodies in fruit bats Filovirus are ancient and integrated into mammalian genomes Charge surrounded pockets and electrostatic interactions with small ions modulate the activity of retroviral fusion proteins Dormant" immunosuppressive domains (ISD) in filoviruses: activation of "Dormant" filoviruses by endogenous retroviruses Immunosuppression during preg nancy and influenza Core struc ture of the envelope glycoprotein GP2 from Ebola virus at 1.9 Å resolution Properties of Ebola virus proteins Ebola response roadmap: Situation report Ebola outbreak in West Africa Ebola virus disease in West Africa: Clinical manifestations and management Filovir idae: Marburg and Ebola viruses Filovirus replication and tran scription GP mRNA of Ebola virus is edited by the Ebola virus poly merase and by T7 and vaccinia virus polymerases T cell immunoglobulin and mucin domain 1 (TIM 1) is a receptor for Zair Ebolavirus and Lake Victoria Marburgvirus Filovirus entry: A novelty in the viral fusion world Filoviral immune evasion mechanisms The Ebola virus VP35 protein functions as a type I IFN antagonist Antigenic subversion: A novel mechanism of host immune evasion by Ebola virus A case of severe Ebola virus infection compli cated by Gram negative septicemia Analy sis of human peripheral blood samples from fatal and nonfatal cases of Ebola (Sudan) hemorrhagic fever: Cellular responses, virus load, and nitric oxide levels Consultation on potential Ebola therapies and vaccines: Background document for participants Ebola haemorrhagic fever Transfectant influenza A viruses with long deletions in the NS1 protein grow efficiently in Vero cells Identifica tion of an antioxidant small molecule with broad spec trum antiviral activity Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate mono cytes/macrophages is a key event Experimental analysis of the possibility to treat MJarburg hemorrhagic fever with Desferal, Ribavirin, and homolohous interferon Pathogenesis of Ebola hemorrhagic fever in primate models: Evidence that hemorrhage is not a direct effect of virus induced cytolysis of endothelial cells Animal models for Ebola and Marburg virus infections Peptide Bβ15 42 preserves endothelial bar rier function in shock Efficiency of tumor necrosis fac tor antiserum in treatment of Marburg hemorrhagic fever Filovirus induced endothelial leakage triggered by infected monocytes/macrophages Effects of Ebola virus glycoproteins on endothelial cell activation and barrier function Ebola and Marburg viruses Recombinant human activated protein C for the pos texposure treatment of Ebola hemorrhagic fever Clini cal presentation and management of severe Ebola virus disease Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: A study in rhesus monkeys Antibody dependent enhancement of Marburg virus infection Antibody dependent enhancement of Ebola virus infection Filovirus tropism: Cellular molecules for viral entry Rekomendatsii po lecheniyu i profilaktike gemor ragicheskoi likhoradki Ebola (Guidelines for Treatment and Prevention of Ebola Hemorrhagic Fever) Laboratory Guid ance for the Diagnosis of Ebola Virus Disease: Interim Recommendations Laboratory detection and diagnosis of filoviruses Ebola: Experimentelles Medikament aus Wien in Frankfurt angewendet Development of therapeutics for treatment of Ebola virus infection Single injection vaccine protects nonhuman primates against infection with Marburg virus and three species of Ebola virus Progress in filovirus vaccine development: Evaluating the potential for clinical use USA focuses on Ebola vaccine but research gaps remain Recombinant vesic ular stomatitis virus based vaccines against Ebola and Marburg virus infections Ebola clinical trials: Big name players in the Ebola race Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge Delayed treatment of Ebola virus infection with plant derived monoclonal antibodies provides protec tion in rhesus macaques Ebola "cocktail" developed at Cana dian and U.S. labs VP35 knockdown inhibits Ebola virus amplification and protects against lethal infection in mice Chemical modifications of antisense morpholino oligomers enhance their efficacy against Ebola virus infection Marburg virus infection in nonhimans primates: Therapeutic treatment by lipid encapsulated siRNA Developing aerosolized TKM EBOLA as airborne transmission of Ebola likely A highly immunogenic fragment derived from Zaire Ebola virus glycoprotein elicits effective neutralizing antibody Ebola drug trials set to begin amid cri sis. Testing drugs in the middle of deadly disease out break is challenging but can be done Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infec tion Protection against filovirus diseases by a novel broad spectrum nucleoside analogue BCX4430 Favipiravir (T 705), a novel viral RNA polymerase inhibitor Successful treatment of advanced Ebola virus infection with T 705 (favipiravir) in a small animal model Post exposure efficacy of Oral T 705 (Favipiravir) against inhalational Ebola virus infection in a mouse model FDA approved selective estrogen receptor modulators inhibit Ebola virus infection Screening of an FDA approved Compound Library identifies four small molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture Small molecules in treatment of sepsis Arbidol inhibits viral entry by inter fering with clathrin dependent trafficking This work was supported by the Russian Science Foundation (project no. 14 13 01301) and the Minis try of Health of the Russian Federation.