key: cord-324295-9c1zxjng authors: Bonilla-Aldana, D. Katterine; Jimenez-Diaz, S. Daniela; Arango-Duque, J. Sebastian; Aguirre-Florez, Mateo; Balbin-Ramon, Graciela J.; Paniz-Mondolfi, Alberto; Suárez, Jose Antonio; Pachar, Monica R.; Perez-Garcia, Luis A.; Delgado-Noguera, Lourdes A.; Sierra, Manuel Antonio; Muñoz-Lara, Fausto; Zambrano, Lysien I.; Rodriguez-Morales, Alfonso J. title: Bats in Ecosystems and their Wide Spectrum of Viral Infectious Threats: SARS-CoV-2 and other emerging viruses date: 2020-08-20 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2020.08.050 sha: doc_id: 324295 cord_uid: 9c1zxjng Bats have populated earth for approximately 52 million years, serving as natural reservoirs for a variety of viruses through the course of evolution. Transmission of highly pathogenic viruses from bats has been suspected and linked to a spectrum of emerging infectious diseases in humans and animals worldwide. Examples of such viruses include Marburg, Ebola, Nipah, Hendra, Influenza A, Dengue, Equine Encephalitis viruses, Lyssaviruses, Madariaga and Coronaviruses, involving the now pandemic Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we provide a comprehensive review on the diversity, reservoirs, and geographical distribution of the main bat viruses and their potential for cross-species transmission. J o u r n a l P r e -p r o o f Bats have populated earth for approximately 52 million years, serving as natural reservoirs for multiple viruses through the course of their existence 7, 8 . The evolution of their physical, physiological and behavioral characteristics has allowed them to expand to all continents except Antarctica, with ecological niches located in urban or rural areas, and especially in caves, mines and some types of foliage 9 . Evolutional changes have also determined their current eating patterns and their role within the ecosystem 10 . Bats are the only mammals capable of flight; they have nocturnal habits during which they either feed or mate and a layer of short fur that protects them from humidity and cold temperatures 11 . Bats belong to the order Chiroptera (wings on the upper extremities), with approximately 1,100 species subclassified into two suborders: the Megachiroptera and Microchiroptera. This classification allows a better understanding of some of their behavioral patterns 8, 12, 13 . Bats from the Megachiroptera suborder, commonly known as megabats, account for approximately 170 species mainly located in Asia, Africa and Oceania or Pacific region ( Figure 1 ); their size can vary between 40 and 150 cm with their wings spread, and they weigh 1 kg on average. Megabats feed exclusively on fruit, seeds and pollen and their main habitats include caves, mines, trees and some buildings. Megachiroptera bats cannot echo localize 8 . The Microchiroptera or microbats include over 930 species distributed throughout the entire planet with the exception of some islands and the poles. Their size ranges from 4 to 16 cm and feed mostly on flowers and fruit. They possess an echolocation system that allows hematophagous bats to search and capture small prey such as lizards, small mammals, and arthropods. Their primary habitats include forests and tropical areas although they are also capable of coexisting with humans in some urban settings 8, 12, 13 . J o u r n a l P r e -p r o o f Another notable feature is that microbats can travel long distances of up to 2000 km during migratory season to fulfill their nutritional needs, which is relevant to understand local and intercontinental spread of colonies and coexistence with other animals of the same species. Microbats also play a role as pollinators as their feces fertilize and distribute seeds among the areas they inhabit, in addition to serving as plague controllers by feeding on insects, frogs, and rats 8, 14 . Bats that coexist within the same geographical area often host common microorganisms 11, 12 . Contagion rates depend on contact speed and susceptibility to infections of a specific population 12 . Evolutionary processes granted bats with hollow bones to facilitate air maneuvering. This hollowness results in the absence of bone marrow and thus the inability to produce B cells necessary for an efficient immune response, making bats asymptomatic carriers for a long list of viruses 8 . Additionally, several species are facultative heterotherms capable of entering profound lethargy during periods of physiological stress to compensate for energy and water deficits, favoring viral persistence 12 . Continuous physical contact within bats of the same colony facilitates viral circulation, especially during breeding and migration seasons 15 . The proposed mechanisms of viral transmission between microbats is aerosol release produced by larynx vibrations that occur during echolocation in addition to close contact with other types of secretions such as fecal matter and urine 16 . Then, bats carry multiple emerging and reemergin pathogens, especially viral threats ( Table 1) . Studies from the EcoHealth Alliance suggest that bats are one of the leading carriers of emerging infectious agents that can potentially affect other mammals, including humans [17] [18] [19] . Although the precise reservoir of SARS-CoV-2 has not been established, a sensible hypothesis is that bats of the genus Rhinolophus ferrumequinum could be at fault: Chinese studies have reported that SARS-CoV-2 is very similar to coronaviruses naturally found in bats; however, these viruses are constantly evolving and mutating, making it difficult to pinpoint an exact reservoir ( Figure 1 ). Since there is no effective treatment or vaccine for COVID-19 to date, strong regulations---including isolation, quarantine and social distancing---have been established by many countries in an effort to reduce expansion of the disease given the high person-to-person transmissibility of SARS-CoV-2, either directly by respiratory droplets with infective particles or indirectly by fluid-contaminated objects. J o u r n a l P r e -p r o o f A study in Indonesia identified CoV genes in bareback fruit bats, where partial RNA-dependent RNA polymerase (RdRp) sequences and regions between helicase and RdRp genes were detected and amplified in faeces and tissue samples 22 . Another study conducted in Zhoushan City, Zhejiang Province, found that out of 334 bats sampled, approximately 26% were naturally infected with Coronaviruses 23 . Marburg virus is an RNA virus belonging to the Filoviridae family (genus Marburgvirus) ( further molecular testing conducted on liver, spleen and lung samples of Egyptian fruit bat Rousettus aegyptiacus reported the presence of MARV RNA ( Figure 1 ). Possible routes of transmission include fruit contamination and its consumption by humans or direct contact with bat's infected organs. MARV can also spread from human to human through contact with bodily fluids or fomites from sick patients (Table 3 ). In humans, the incubation period ranges from 3 to 9 days, and clinical presentation usually involves flulike symptoms, fever between 39 and 40 degrees Celsius, conjunctivitis, cramps, cervical lymphadenopathy, and hemorrhagic manifestations. Death occurs as a consequence of cardiocirculatory collapse and multiple hemorrhages in the digestive tract and lungs. A study detected a high seroprevalence of antibodies against Marburg virus in fruit bats in South Africa, with a 19.1% seroconversion rate in recaptured bats 24 ; Another study detected MARV genome in bats captured in Zambia 25 ; and a posterior serosurvey identified filovirus-specific immunoglobulin G antibodies in 71 out of 748 serum samples collected from migratory fruit bats 26 . Currently, there is no effective treatment for MARV infection other than symptomatic support and rehydration, but some hematologic, immunologic, and pharmacologic actions are under development to improve survival rates. Ebola virus also belongs to the Filoviridae family and displays a negative-stranded single RNA genome. First described in 1976 in the Democratic Republic of the Congo, this notorious virus has decimated populations of gorillas, chimpanzees and humans in Africa with mortality rates ranging from 25% to 90% (Table 2) . Evidence of infection has been reported in three different species of frugivorous bats associated with large outbreaks of Ebola hemorrhagic fever in 2014-2015, which later escalated to pandemic proportions resulting in the death of 11,301 people 8, 27 . Multiple studies point at bats of the genus Myotis as the main reservoir for Ebola virus given that these bats carry a copy of viral gene VP35 (Table 3) Studies in Africa analyzed 4,022 blood samples from bats, detecting antibodies against Ebola virus in one genus of insectivorous bats and six species of fruit bats 29 . Another study conducted in Sierra Leone identified the complete genome of a new Ebola virus, the Bombali virus, in free-tailed bats resting inside human dwellings, suggesting potential human transmission 30 . In Kenya, researchers also identified the Bombali virus in the organs and excreta of free-tailed bats (Mops condylurus) 31 . In Malaysia, an outbreak in pigs and humans took place between September 1998 and April 1999, affecting 283 people and causing 109 human deaths and the slaughter of more than one million pigs (Table 2) . Initially, the outbreak was attributed to the Japanese encephalitis virus; but later, researchers demonstrated that the causal agent was a virus that belonged to the Henipavirus genus, family Paramyxoviridae, closely related to the Hendra virus. Fruit bats (genus Pteropus) are the main natural reservoir for Nipah virus (NiV), while pigs serve as intermediate hosts ( Table 3 ). The infection is transmitted from bats to pigs and subsequently from pigs to humans ( Figure 1 ). On the Island of Malaysia, researchers found NiV in the urine and saliva of flying foxes (Pteropus hypomelanus and Pteropus vampyrus). Initial circulation of NiV likely occurred in late 1997 through contaminated food debris from migrating flying foxes on which pigs fed. Fruit bat migration to cultivated orchards and pig farms was a consequence of the lack of fruit during droughts related to El Niño phenomenon and wild fires in Indonesia. A study conducted in 324 bats (predominantly Pteropus, P. vampyrus and P. hypomelanus) from Malaysia found that 6.48% had neutralizing antibodies against NiV and the virus was subsequently isolated from the urine and fruits consumed by P. hypomelanus. Previous human studies showed that most cases had a history of direct contact with live pigs. In humans, the disease can be fatal and is characterized by respiratory and particularly severe neurological manifestations, such as encephalitis and coma. Clinical signs in animals may vary, including agitation, spasms, seizures, rapid breathing, and harsh cough. Evidence of infection (virus isolation, immunohistochemistry, serology) and neurological involvement has been reported in dogs and horses. Transmission studies in Australia established that NiV could rapidly spread through pigs via oral and parenteral inoculation. Neutralizing antibodies were detectable 10-14 days after infection [32] [33] [34] [35] [36] . Influenza A viruses (IAV) are one of the leading causes of disease in humans, with important animal reservoirs including birds, pigs, and horses that can potentially produce new zoonotic variants (Table 2) . (Table 3) . Notably, small yellow-shouldered bats in Central America have been proposed as potential mammalian reservoirs of influenza (Figure 1 ). Research has shown that bats are susceptible to IAV infection. A seroprevalence study identified IAV H9 in 30% of fruit bats sampled in Africa. Bats are believed to have the ability to harbor more genetic diversity of the Influenza virus than any other mammal and bird species. J o u r n a l P r e -p r o o f Hendra virus, formerly known as equine morbillivirus, is a henipavirus of the Paramyxoviridae family for which bats of the genus Pteropus serve as main vectors (Table 2) . This virus is endemic in Australian flying foxes which are currently in danger of extinction and it can be detected in blood, urine, faeces, and fetal and uterine tissue. Different studies affirm that Hendra virus is horizontally transmitted from bat to bat, but in rare instances vertical transmission has been reported ( Figure 1 ). Although horses are usually accidental hosts that can contract the virus from these megabats, it has been suggested that the virus could be found in the environment, entering equines through the upper airways and oropharynx. Transmission to humans occurs with close contact with infected horses, either through bodily fluids or aerosols; studies have ruled out person-to-person transmission. Hendra virus was discovered after an outbreak that killed 20 equines and their trainer in Queensland, Australia, in 1994 37 . The virus remains viable for approximately four days in bat urine and fruit juice, but fails to survive in temperatures above 37 degrees Celsius. The disease has an incubation period of 5-12 days, and its main symptoms are similar to influenza but with a mild, progressive encephalitis. Since this infection is uncommon in humans, an effective antiviral has not been developed (Table 3) . Lyssaviruses are a wide range of pathogens that cause rabies ( Table 2 ). The first case of human rabies was reported in Ukraine in 1977. Hematophagous bat Desmodus rotundus, mainly located in Latin America ( Figure 2) , is considered the primary vector of this disease, which historically has resulted in large economic losses by causing the death of cattle and horses that get infected through bat bites. Occasionally, those bites are also seen in human beings (Figures 3-4) . Lyssaviruses have also been identified in other hematophagous bats such as Diphylla ecaudata and Diaemus youngi and frugivorous species such as Artibeus, Planirostris trinitalis, Diclidurus albus, Hemiderma sp. and Phyllostoma superciliatum (Table 3) . A Colombian study performed on 286 brains from bats of six families and 23 species showed that two species, Artibeus lituratus and Artibeus planirostris, were positive for the rabies virus 38 . Another study conducted in Chile reported that 9.5% of 15,000 bats captured were naturally infected 39 As a consequence of the destruction of natural habitats, closer interaction between bats and humans has grown significantly, especially in mining areas 44 . Rabies transmission primarily occurs via direct bites or scratches from infected bats 38 ; secondary transmissions in humans takes place through contact with infected pets. These viruses cause acute progressive encephalitis that is inevitably fatal from the onset of clinical signs. Initial symptoms are similar to influenza and evolve in a few days to severe neurological involvement that ultimately leads to death 45, 46 . Currently, only preventive vaccines are available [47] [48] [49] [50] [51] . Dengue virus (DENV) belongs to the Flaviviridae family, which is transmitted by mosquitoes, most commonly Aedes aegypti ( Table 2) 52 . There are four DENV serotypes (DENV-1, DENV-2, DENV-3 and DENV-4) that can cause febrile syndromes in humans. Dengue fever is recognized as an epidemic reemerging disease that has affected many countries in recent decades 53-57 . There is evidence that bats could naturally become infected with DENV 58 . In Mexico, a study evaluated 162 bats and identified DENV nucleic acid and anti-DENV antibody 59 . Another study in Costa Rica evaluated 12 species of bats, reporting a cumulative seroprevalence of 21.2% (51/241) by PRNT and a J o u r n a l P r e -p r o o f prevalence of 8.8% (28/318) in organs tested by RT-PCR 60 . In French Guiana, DENV nucleic acid was detected in the liver and sera of wild-caught bats 61 . Recently in Colombia, viral RNA was obtained from bat tissues, and a nested-RT-PCR detected amplicons of 143 fragment of the NS5 gene that were then sequenced by the Sanger method. In non-hematophagous bats such as Carollia perspicillata and Phyllostomus discolor captured in Ayapel and San Carlos (Córdoba) respectively, an amplicon corresponding to NS5 was detected; these amplicons showed high similarity with DENV-2 57 . Yet, the clinical relevance of DENV isolation from bats is unclear, as well as the implications in transmission to humans. Similarly occurs with other arboviruses, such as Madariaga and the Equine Encephalitis viruses. So far, the have been confirmed as infected hosts, probably reservoirs, but not a direct source for human infections (Figure 1 ). The equine encephalitis group involves RNA viruses belonging to the Togaviridae family, of the Alphavirus (Table 3 ). These findings suggest that fruit bats from the Caribbean region in Colombia could be involved in the enzootic cycle of EEV 62 (Figure 1 ). The Madariaga virus is a strain of the eastern equine encephalitis virus. Rats and bats presumably serve as the main vectors given the reported seropositivy of brown short-tailed bats (Carollia castanea), Lanza bats (Phyllostomus discolor) and Seba's short-tailed bats (Carollia perspicillata) 65 . Several factors increase the interaction between humans and bats. In most cases, this is due to the intrusion of humans into virgin territories inhabited by bats, fueled by the search of economical resources. This J o u r n a l P r e -p r o o f phenomenon forces bats to adapt to new settings occupied by men, such as buildings, tombs, mines and bridges. Additional illegal trading of bats for human consumption and traditional medicine in Asia, coupled with poor sanitation and hygiene practices, has facilitated the emergence of zoonotic diseases, some with pandemic potential. Financial openness and globalization involve close connections between countries and across continents and can serve as a mean of transportation that accelerates the spread of these emerging diseases. Emerging diseases are a global matter of concern, especially during the last decades, and now even more with the occurrence of the 2020 pandemic of COVID-19. SARS-CoV-2 and other emerging pathogens are significantly present in bats. Recognizing bats as potential reservoirs or transmission sources for several pathogens that can be a threat to human beings is of upmost importance for global health since many of these conditions may cause severe damage and even led to death, in some cases in a significant proportion of individuals. However, we should not neglect the responsibility of the active role of humans in the invasion of natural habitats and illegal trafficking of bats. 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