Bat-borne virus diversity, spillover and emergence

Letko, Michael; Seifert, Stephanie N.; Olival, Kevin J.; Plowright, Raina K.; Munster, Vincent J.

doi:10.1038/s41579-020-0394-z

Bat-borne virus diversity, spillover and emergence

Review Article
Published: 11 June 2020

Volume 18, pages 461–471, (2020)
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Bat-borne virus diversity, spillover and emergence

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Abstract

Most viral pathogens in humans have animal origins and arose through cross-species transmission. Over the past 50 years, several viruses, including Ebola virus, Marburg virus, Nipah virus, Hendra virus, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory coronavirus (MERS-CoV) and SARS-CoV-2, have been linked back to various bat species. Despite decades of research into bats and the pathogens they carry, the fields of bat virus ecology and molecular biology are still nascent, with many questions largely unexplored, thus hindering our ability to anticipate and prepare for the next viral outbreak. In this Review, we discuss the latest advancements and understanding of bat-borne viruses, reflecting on current knowledge gaps and outlining the potential routes for future research as well as for outbreak response and prevention efforts.

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Introduction

Bats are the second most diverse mammalian order on Earth after rodents, comprising approximately 22% of all named mammal species, and are resident on every continent except Antarctica¹. Bats have been identified as natural reservoir hosts for several emerging viruses that can induce severe disease in humans, including RNA viruses such as Marburg virus, Hendra virus, Sosuga virus and Nipah virus. In addition to direct isolation of these human pathogens from bats, accumulating evidence suggests that other emerging viruses, such as Ebola viruses, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2 and Middle East respiratory coronavirus (MERS-CoV), also originated in bats, even if other hosts, such as civets for SARS-CoV and camels for MERS-CoV, are proximate reservoirs for human infection^2,3,4,5. A growing list of emergent coronaviruses, including the Swine acute diarrhoea syndrome coronavirus, which emerged from horseshoe bats and killed >20,000 pigs⁶, and the ongoing COVID-19 pandemic^{36,43,60,120,171,172,173,174}. These studies have led to valuable discoveries, for example, showing that R. aegyptiacus, from which Marburg virus was isolated, is refractory to infection with many other viruses that are associated with other bat reservoir species^{19,44,45,120,121}, making the broad use of this bat species in disease pathology modelling questionable. Beyond the technical challenges of working with these animals, a bigger issue with bats as animal models lies in our fundamental approach to disease modelling: almost all currently established animal models in virology are centred on severe disease phenotypes and high levels of viral replication. This custom contrasts with our current understanding of bat virus biology, which assumes that bats exhibit minimal pathology and likely low levels or short temporal bursts of viral replication. Recent experimental infection studies with Tacaribe virus and Lagos bat virus in their respective natural reservoir bat species^175,176 resulted in severe disease and mortality, showing that the paradigm that bats are resistant to highly pathogenic viruses should be addressed at the level of specific host–pathogen interactions rather than as a generalization for a complete animal order. Comparative studies between animal models of human disease and bat animal models are needed to understand the mechanisms responsible for the differences in disease severity of bat-borne viruses observed in natural reservoir and spillover host species.

Viral spillover from bats

The spillover of bat-associated viruses requires a combination of factors, including ecological opportunity for contact, virus–host molecular and cellular compatibility, and a permissive or circumvented immune response, as described in detail herein. Yet, despite the various potential barriers and the fact that many spillover events may go undetected by surveillance systems, there is a growing list of recent bat-borne zoonotic spillover events. This list includes examples of direct bat-to-human spillover, which are supported by both epidemiological evidence and molecular detection of monophyletic viruses between bat and human populations; the examples include near annual outbreaks of Nipah virus in Bangladesh since 2001 (ref.⁶⁸), several Marburg virus outbreaks across Africa² and outbreaks of rabies virus and other novel Lyssaviruses globally. Other examples of indirect bat-to-human spillover that involve intermediate hosts are also supported by epidemiological and molecular evidence, including Hendra virus in 1994 via horses⁶⁹ and Nipah virus in Malaysia in 1997 and 1998 via pigs⁷⁰. The SARS-CoV 2002–2003 outbreak in southern China and the 2019 SARS-CoV-2 emergence in central China were retrospectively connected to bat populations via molecular evidence and appeared to involve intermediate hosts. Several viruses closely related to SARS-CoV were found in bats, and actual SARS-CoV was directly isolated from animals in open-air markets^14,63,71. Analogously, several bat viruses have now been identified to have a high similarity to SARS-CoV-2 (ref.⁷²). In several other cases, bat-to-human spillover was assessed retrospectively via serological human cohort studies; for example, Henipavirus spillover among bat hunters in Cameroon⁷³, bat-borne reovirus (Melaka virus and Pulau virus) exposure in people living in close proximity to bat roosts on Tioman Island, Malaysia⁷⁴, as well as in a random sample screened in Singapore⁷⁵, Filovirus exposure of bat hunters in India⁷⁶ and ongoing human exposure to SARSr-CoVs in rural communities in China occurring after the 2003 SARS outbreak⁷⁷.

Molecular biology of transmission

All viruses, regardless of classification or origins, must be able to subvert and overcome various molecular factors within their hosts in order to replicate and spill over into new species. Every stage of the viral life cycle relies on numerous protein interactions with the host cell, including viral binding and entry, recruitment of host factors essential for viral replication, suppression of antiviral host factors, assembly and egress from the cell, and evasion of the host immune system⁷⁸ (Fig. 2). Viral–host protein interfaces have been shown, through functional and structural studies, to be remarkably specific and involve multiple points of contact⁷⁹. Even single amino acid variations can impact or abrogate a viral–host protein interaction between different species and form a molecular block, or species barrier, to viral replication^{80,81,82,83,84,85}. The complexity of viral–host protein interactions is compounded by how many interactions occur during any given infection. Recent proteomics studies have identified at least 194 protein interactions between Ebola virus and human host cells⁸⁶, 198 virus–host protein interactions for Zika virus⁸⁷, 101 for Nipah virus⁸⁸ and over 300 for influenza A virus⁸⁹. Given that even small perturbations in these complex networks of virus–host interactions can make the difference between a dead-end infection or viral emergence in a new host species, it is likely that the majority of bat-borne viruses fail to infect novel species as a result of within-host barriers^90,91.

**Fig. 2: Overview of molecular host species barriers.**

Cell entry of zoonotic viruses

One of the first major virus–host protein interactions that occurs during the course of infection is at the level of viral cell entry, when the virus interacts with the host receptor to facilitate the release of viral components into the cytoplasm. Depending on the virus, this process can involve one or more viral proteins, one or more host components and encompass several steps occurring at the cell surface or at an internalized membrane.

It is not surprising that many bat-borne zoonotic viruses have evolved to use highly conserved host molecules for cell entry that have little genetic variation between different species. Henipaviruses bind to the ephrin family of signalling proteins^92,93,94, Filoviruses bind to the cholesterol transporter Niemann-pick C1 (NPC1)^95,96 and Betacoronaviruses have been shown to bind different common cell-surface proteases, including angiotensin-converting enzyme 2 (ACE2) in the case of SARS-CoV and SARS-CoV-2 (ref.⁹⁷) and dipeptidyl peptidase IV (DPP4) in the case of MERS-CoV⁹⁸. Indeed, these receptors are nearly identical, at least in the regions that interact with the virus, between various bat species, intermediate host species, such as camels and palm civets, and humans^84,85,99.

Restriction of cell entry is not easily overcome by viruses. For example, wild-type mice are completely resistant to infection with MERS-CoV because of differences in murine DPP4 glycosylation from human DPP4 (ref.¹⁰⁰). Despite great effort from the animal disease-modelling community, to date, there is no MERS-CoV isolate that can use wild-type murine DPP4, likely because too many viral adaptations are necessary. However, partial blocks to cell entry are more easily overcome. Recently, it has been shown that MERS-CoV can rapidly acquire single-point mutations to increase its compatibility with DPP4 from different bat species⁸⁵. Some MERS-related CoVs discovered in bats, which appear nearly identical to MERS-CoV over most of the genome, have mutations at key binding sites across the receptor-binding spike glycoprotein and are thus unable to bind to human DPP4 (ref.⁶⁴). Similar types of viral adaptation have been observed for other zoonotic viruses such as SARS-CoV¹⁰¹, parvoviruses¹⁰² and avian influenza A virus¹⁰³. Taken together, the ability to use conserved host receptors and readily adapt to receptor variation between species are two hallmarks of viruses that have spilled over into the human population.

The genetic diversity of many RNA viruses can be attributed to high mutation rates, short generation times and the strong selective pressure of the host environment (during natural infections or after vaccinations); however, positive-stranded RNA viruses, including SARS-CoV and MERS-CoV, have relatively low mutation rates associated with 3′–5′ exoribonuclease proofreading activity^{104,105,106,107,108}. The rapid evolution of coronaviruses to the host environment is largely driven by the high rates of genetic recombination, which facilitate the acquisition of multiple mutations in a single event. Inheriting multiple genetic changes at once can have dramatic effects on viral replication and subsequent adaption to new host environments. Recent phylogenetic analyses have revealed that the variation in MERS-CoV circulating in camel populations is largely driven by recombination^{109,110,111,112}. Although SARSr-CoVs have been identified and isolated from bats, no single bat isolate perfectly matches the human strains. For example, some SARSr-CoVs can use the human receptor but vary drastically from SARS-CoV in the 3′ end of their genome, whereas other SARSr-CoVs are nearly identical to SARS-CoV in this region but fail to interact with the human receptor¹¹³. In further support of these findings, the entire SARS-CoV genome has now been sequenced across multiple separate but related viruses circulating in bats, strongly suggesting that the human virus is a recombinant form of these ancestral variants¹¹⁴. Outside coronaviruses, recombination in the rabies virus glycoprotein was shown to facilitate cross-species transmission from bats to skunks and raccoons¹¹⁵. Thus, in addition to the rapid mutation rate characteristic of many RNA viruses, recombination provides an additional mechanism to rapidly overcome barriers in novel host species.

Post-entry virus–host interactions of zoonotic viruses

Whereas our understanding of viral entry as a species barrier is becoming clearer for many emerging zoonotic viruses, cellular blocks beyond entry are more elusive and remain largely unknown. However, research over the past 20 years with well-studied zoonotic pathogens, such as lentiviruses, including HIV and its evolutionary predecessor simian immunodeficiency virus, and influenza A virus, which includes avian influenza A virus, has led to the identification of numerous human and primate intracellular species barriers in the form of dependency factors, which these viruses rely on to replicate, and restriction factors, which are antiviral proteins that specifically interfere with viral replication¹¹⁶. For example, the ability of the simian immunodeficiency virus accessory protein Vif to antagonize the host restriction factor APOBEC3 is vital in determining the potential host breadth in non-human primates^117,118. The avian influenza A virus accessory protein PB1-F2 disrupts mitochondrial antiviral signalling more efficiently in the avian host than the truncated PB1-F2 common in mammalian influenza A viruses¹¹⁹. Although the post-entry species barriers that limit host breadth for lentiviruses and influenza viruses are likely different from those that limit host breadth for the emerging bat-borne infectious diseases, the research framework for these well-studied host–pathogen systems can serve as a roadmap for research into bat-borne host–pathogen systems.

Recent experimental infection studies in bats provided evidence of species-level post-entry barriers, suggesting that some bat-borne viruses are likely host specific and may have a limited ability to transmit between certain bat species. For example, the Rhinolophus spp. bat coronavirus WIV1-CoV and Ebola virus can use the cellular receptors from R. aegyptiacus bats to enter cell lines, but these bats fail to support any WIV1-CoV infection and only poorly support Ebola virus replication^84,120,121. Transcriptomics studies have identified several immune signalling pathways that are activated differently in human versus Rousettus spp. cells^51,52. Other studies have taken more direct approaches to identify post-entry barriers to replication. Mass spectrometry has pinpointed the host E3-ubiquitin ligase, RBBBP6, as a negative regulator of Ebola virus transcription, which functions by binding VP30, a viral protein that is key in replication⁸⁶. A similar study found that the key Ebola virus protein involved in antagonizing the host interferon pathway, VP35, forms an essential interaction with host TRIM6 protein and that the disruption of this interface reduces viral replication¹²². Additionally, tetherin^123,124,125 and IFITM host proteins¹²⁶, which have been shown to inhibit lentiviruses and influenza A virus, respectively, have broad antiviral effects to Ebola virus and SARS-CoV. Tetherin from fruit bats inhibits Nipah virus but not Ebola virus¹²⁷. Compared to more well-studied viruses with a zoonotic origin, such as influenza A virus and HIV, there is still much to uncover for post-entry species barriers of emergent, bat-derived viral pathogens. Large-scale CRISPR–Cas9-mediated knockout and activation screens in human cells have recently identified specific host factors that are essential to flaviviruses^128,129,130, HIV¹³¹, Epstein–Barr virus¹³² and influenza A virus^133,134 but such data have not yet been generated for bat-derived viruses.

Moving beyond virus discovery

Worldwide consortiums such as the USAID PREDICT programme as well as many independent academic laboratories around the world have used a combination of consensus PCR screening and deep sequencing to characterize thousands of novel viral sequences in samples taken from healthy bats¹³⁵. Many of these novel viruses, or viral fragments, are phylogenetically related to pathogens of interest to public health; however, the capacity for these novel viruses to cause future outbreaks typically remains unresolved. With viruses isolated or sequenced directly from bat samples and molecular approaches, including viral pseudotype studies and reverse genetics, researchers have been able to demonstrate the potential of novel viruses to replicate in human cells or use human receptors for entry — the first step to incorporate virus discovery into a more comprehensive risk-reduction framework^14,63,136 (Fig. 3). Characterizing the breadth of naturally occurring bat-borne viruses, including close relatives to human viruses, is critical and leads to important insights. For example, the discovery and subsequent investigations of a novel non-pathogenic henipavirus¹³⁷, Cedar virus, related to Nipah virus and Hendra virus, have proved invaluable in revealing the genetic determinants of pathogenicity in henipaviruses. Unlike Nipah virus, Cedar virus does not produce V or W proteins, which are responsible for antagonizing the host interferon pathway, and it also relies on different host cell receptors¹³⁸. The identification of viruses related to Ebola virus in various bat species, including the novel Bombali virus, has provided additional support for bats as reservoirs for Ebola viruses and, even though there are no reports of filovirus haemorrhagic fever in China, filoviruses have also been identified in Rousettus spp. bats in China¹³⁹. Thus, further research is needed to confirm host species range and the potential for human infection²⁵. Ancestral variants of zoonotic coronaviruses similar to SARS-CoV, MERS-CoV and SARS-CoV-2 have been identified from bats, with some viruses related to SARS-CoV even being capable of using the human receptor ACE2 (refs^{14,63,72,114,140}). Although both SARS-CoV and MERS-CoV have also been isolated from intermediate hosts (palm civets¹⁴¹ and camels¹⁴², respectively), it is possible that these two viruses can be directly transmitted to humans from bats.

**Fig. 3: Using functional viromics to move beyond zoonotic virus discovery.**

Linking surveillance and control

Although whole genome data are needed for downstream and comparative studies, even knowing the taxonomic family of a novel pathogen causing an outbreak can help narrow down control and treatment strategies. Novel diagnostic platforms such as the GeneXpert^TM (Cepheid Inc.), which is a semi-automated PCR-based test, enable rapid, multiplexed detection of a wide panel of human pathogens and are constantly being improved to increase sensitivity and pathogen coverage. Virus discovery efforts are producing a wealth of genome sequencing data that are then made publicly available through online data repositories. Pan-serological assays are also facilitating virus discovery and providing insights into antibody cross-reactivity⁷⁷. The resulting datasets provide insight into the existing variation in viral families, allowing for the development of diagnostic and surveillance assays broadly targeting virus clades. For example, Bombali ebolavirus was initially discovered in bat samples using a consensus PCR assay²⁵ developed to target a region of the viral genome for which the nucleic acid sequence is conserved between related viruses. The identification of key reservoir species and the development of better models to predict virus spillover events could enable targeted prophylactic vaccination campaigns of humans and potential reservoir hosts or intervention strategies to minimize contact between bats and humans. For example, high-risk populations that geographically overlap and have high levels of contact with bats and other wildlife could be vaccinated against Ebola virus to prevent outbreaks rather than responding to them after spillover, and local communities could benefit from education campaigns on how to live safely around bats and reduce direct contact¹⁴³. Alongside these measures, efforts should be taken to reduce bat habitat destruction, which results in increased contact between bats and humans and is considered a cause of viral spillover¹⁴⁴.

Next-generation vaccine technologies are platforms that are broadly and rapidly adaptable for different types of viral pathogens. Importantly, several of these platforms use genetically modified viruses, such as the vesicular stomatitis virus (VSV) and ChadOx1 platforms, which can induce protective immunity in humans, mice, guinea pigs, non-human primates and livestock^145,146,147 to a number of pathogens, including bat-borne Ebola virus and Nipah virus. Vaccine efficacy in animals, for example, horse vaccination for Hendra virus, including livestock and other peri-domestic animals, may even enable proactive measures to reduce cross-species transmission of bat viruses to humans¹⁴⁸. Although still nascent and only in early clinical trials, novel platforms such as DNA-based and mRNA vaccines offer the potential for an incredibly rapid response time from pathogen discovery to therapeutic intervention. Using these technologies, researchers were able to test the first Zika vaccine in mice and non-human primates within 3.5 months of the initial outbreak in 2015 and, more recently, a similar RNA-based vaccine was designed for SARS-CoV-2 and entered human clinical trials only 2 months after the virus sequence was published¹⁴⁹. Other platforms based on VSV or adenovirus are already FDA approved and have been shown to be effective in several species and for most of the major emerging viruses identified to date.

Depending on the route of transmission, pre-emptive control strategies may also include low-cost, low-technology (that is, ecological) countermeasures. For example, Nipah virus is believed to be transmitted to humans through date palm sap collection containers that have been contaminated with virus-containing urine from visiting fruit bats¹⁵⁰. One proposed intervention is covering the containers to prevent bat feeding and contamination with bat urine¹⁵¹. Proactive wildlife and livestock mortality surveillance, such as great ape Ebola virus carcass surveillance in the Republic of the Congo, could function as an early warning system preceding spillover to the human population¹⁵².

Challenges to outbreak control

‘One Health’ approaches involve addressing zoonosis at the human, animal and environmental levels. One of the biggest hurdles to preventing zoonosis at the animal level is the limited feasibility of wildlife vaccination. Given that filoviruses and coronaviruses are likely hosted in a variety of different animal populations, including multiple bat species and other mammals, covering large geographic regions, current vaccination delivery methods are impracticable and likely insufficient to induce effective herd immunity. Although effective vaccines are now in development for Ebola virus, Hendra virus and rabies virus, there are no effective vaccines currently available for both human and animal use. Some progress has been made on this front, for example, in the form of oral vaccines against rabies in dogs¹⁵³ and bats¹⁵⁴ as well as against plague in black-tailed prairie dogs¹⁵⁵. Applying similar efforts to other viruses in lesser-studied and more remote bat populations and other mammals will require a greater understanding of host ecology and behaviour.

After it was discovered that horses are susceptible to Hendra virus and can amplify the virus and infect humans, the Australian government invested in develo** a highly effective vaccine that could be given to horses¹⁵⁶. It was hoped that reducing transmission of the virus to horses would reduce transmission to humans. However, vaccination efforts in Australia have been hindered by antivaccination sentiment, the public perception of the vaccine being too costly for such a rare pathogen and by anecdotal evidence of unwanted side effects. This lack of adoption of Hendra virus vaccination has allowed for sporadic Hendra virus outbreaks in horses to continue¹⁵⁷, threatening human and animal health.

The geopolitical climate represents an even bigger challenge to outbreak prevention. Despite the existence of multiple, experimental therapeutic options, the latest Ebola virus outbreak in the Democratic Republic of Congo (ongoing since 2018) has been stymied by civil war breaking down the health-care system and militant groups targeting health-care workers and outbreak response teams¹⁵⁸. The recombinant VSV Ebola virus vaccine has been successfully used in response to Ebola virus outbreaks and is now FDA approved. The full licensure of the VSV vaccine will allow for a broader pre-emptive rather than reactive vaccination approach and marks the first licensure of a human vaccine for a bat-borne infectious disease since rabies. Another example of geopolitical disruption was seen during the emergence of SARS-CoV in China in 2002, when the Chinese government delayed reporting the health crisis to the international community well after the outbreak had begun to spread¹⁵⁹. The timely release of public health data remains a critical issue during the current COVID-19 pandemic and appears to have improved with the release of case data and full genome viral sequences as the outbreak develops (novel 2019 coronavirus on virological.org).

Conclusions

Disease X, or the as yet unknown pathogen poised to cause the next pandemic, poses a grand challenge in outbreak prevention and response. Bats represent an important but largely uncharacterized source of known human pathogens. Despite a limited understanding of bats, the viruses they carry, and the molecular and ecological forces driving viral spillover, the tools to develop next-generation vaccines and antiviral technologies are maturing such that researchers will be able to respond to the next outbreak with unprecedented speed. In order to transition bat virus research from reactive to predictive with the ability to determine which pathogens represent the greatest threat to global health, vast advancements are needed across a multitude of disciplines (Box 3). Here, we have identified the important progress made in the past decade and the gaps remaining in our understanding of bat virus ecology, genetic diversity and the molecular mechanisms underlying zoonotic infection and immunity. The emergence and re-emergence of zoonotic bat pathogens demonstrates the inextricable link between the health of humans, animals and the environment. Therefore, efforts to mitigate the public health impacts of bat-borne viruses must integrate research across these disciplines, applying a ‘One Health’ approach, from field to lab, to address the problem. The future of bat virus research lies in a combined and concerted effort to evaluate the molecular and macro-ecological risk factors of transmission, shine light on which viruses carry the potential to spill over and conduct large-scale, longitudinal surveillance studies that will support the deployment and evaluation of next-generation interventions. Nevertheless, the emergence of SARS-CoV-2 continues to present new and sobering challenges. The ongoing COVID-19 pandemic has clearly demonstrated that a dramatic increase in knowledge on pathogen emergence combined with a rapid all-out aggressive response aimed at tracing zoonotic spillover events is needed to prevent the repetition of current events.

Box 3 The future of bat virus research

There is a growing anxiety in the field that merely identifying all the novel animal-derived viruses will do little to prevent the next outbreak. This is in part due to the near total lack of downstream assays to functionally characterize these viruses at the scale at which they are discovered. Thus, most studies have focused on animal viruses that already bear close resemblance to known human pathogens. One avenue for future research efforts should focus on the development of scalable tools that can functionally assess important questions related to viral zoonosis such as whether or not novel bat viruses can infect human cells or use known human receptors. With the cost of gene synthesis decreasing as the technology advances, novel viral glycoprotein sequences could be synthesized in bulk and tested in vitro, for example. Recently, we described a platform to test coronaviruses in bulk scale for their receptor usage¹⁴⁰. Beyond functional studies, disease ecology and modelling are essential to determine the true risk of cross-species transmission, as are better collaborations between bat biologists and disease experts¹⁷⁷. Recent advances in the miniaturization of device technology have produced smaller GPS trackers and more efficient, higher resolution camera traps that will certainly help improve our understanding of host species distribution and key interactions at the bat–human–environment interface. These devices are slowly being deployed in the field to increase our understanding of bat migratory patterns and bat–environment interactions. New weather and environmental satellites are providing a finer resolution of global climate trends, urbanization and development. In addition, open-access datasets of host–virus associations combined with new analytical approaches, for example, machine learning, are expanding our understanding of virus host ranges beyond the limits of current surveillance data^9,168. Collectively, such information is advancing our ability to pinpoint potential hotspots of zoonotic spillover and identify new host reservoirs.

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Acknowledgements

This work was supported (in part) by the Intramural Research Program of the NIH. V.J.M. and R.P. are supported by the DARPA PREEMPT Program Cooperative Agreement (No. D18AC00031). K.J.O. is supported by the USAID Emerging Pandemic Threats PREDICT program, NIH/NIAID award R01AI110964 and a US Defense Threat Reduction Agency award HDTRA11710064.

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Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, National Institutes of Health, Hamilton, MT, USA
Michael Letko, Stephanie N. Seifert & Vincent J. Munster
Paul G. Allen School for Global Animal Health, Washington State University, Pullman, WA, USA
Michael Letko
EcoHealth Alliance, New York, NY, USA
Kevin J. Olival
Department of Microbiology and Immunology, Montana State University, Bozeman, MT, USA
Raina K. Plowright

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Michael Letko
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Stephanie N. Seifert
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Glossary

Life history traits: Traits including, but not limited to, the timing and frequency of reproduction, lifespan, sex ratio and sociality.
Herd immunity: Indirect, reduced risk of infection among susceptible individuals within a population as a result of the majority of that population having immunity through vaccination or a history of exposure or infection.
Susceptible-infectious-resistant framework: A class of compartmental model used in understanding the dynamics of infectious disease in a population.
Type I interferon: A large group of related cytokines that bind to widely expressed interferon-α receptors and are responsible for regulating the immune response to infection.
Type III interferon: A small group of related cytokines that bind to the interferon-λ receptors found on epithelial cells and are responsible for regulating the immune response to infection.
Bat1K project: A global research initiative to sequence and annotate the genomes of all bat species, starting with more than 1,000 of the most relevant species for global health.
Monophyletic: Multiple organisms all derived from a single common ancestor.
Viral pseudotype: A genetically modified virus that has incorporated the glycoprotein of another virus and can produce a measurable reporter, such as GFP or luciferase, upon infection of a cell.
Reverse genetics: Experimentally introducing mutations into the genetic sequence of proteins or whole virus and subsequently testing for the effect on various phenotypes either in cell culture or in animals.

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Letko, M., Seifert, S.N., Olival, K.J. et al. Bat-borne virus diversity, spillover and emergence. Nat Rev Microbiol 18, 461–471 (2020). https://doi.org/10.1038/s41579-020-0394-z

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Accepted: 22 May 2020
Published: 11 June 2020
Issue Date: August 2020
DOI: https://doi.org/10.1038/s41579-020-0394-z
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COVID-19

Series 31 March 2022
Outbreaks and emerging infections

Collection 17 February 2021

Bat-borne virus diversity, spillover and emergence

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Abstract

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Molecular detection of rickettsial agents in Amblyomma maculatum ticks (Ixodida: Ixodidae) from Ecuador

Canine morbillivirus (CDV): a review on current status, emergence and the diagnostics

Evolution and implications of SARS-CoV-2 variants in the post-pandemic era

Introduction

Viral spillover from bats

Molecular biology of transmission

Cell entry of zoonotic viruses

Post-entry virus–host interactions of zoonotic viruses

Moving beyond virus discovery

Linking surveillance and control

Challenges to outbreak control

Conclusions

Box 3 The future of bat virus research

References

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COVID-19

Outbreaks and emerging infections

Navigation

Bat-borne virus diversity, spillover and emergence

From

Abstract

Similar content being viewed by others

Molecular detection of rickettsial agents in Amblyomma maculatum ticks (Ixodida: Ixodidae) from Ecuador

Canine morbillivirus (CDV): a review on current status, emergence and the diagnostics

Evolution and implications of SARS-CoV-2 variants in the post-pandemic era

Introduction

Viral spillover from bats

Molecular biology of transmission

Cell entry of zoonotic viruses

Post-entry virus–host interactions of zoonotic viruses

Moving beyond virus discovery

Linking surveillance and control

Challenges to outbreak control

Conclusions

References

Acknowledgements

Author information

Authors and Affiliations

Contributions

Corresponding authors

Ethics declarations

Competing interests

Additional information

Publisher’s note

Related links

Glossary

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