https://pmc.ncbi.nlm.nih.gov/articles/PMC7289071/
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.
Subject terms: Viral infection, Viral reservoirs, Ebola virus, SARS-CoV-2
Bats harbour a large number of different viruses, some of which have spilled over to cause human disease. In this Review, Letko, Munster and colleagues discuss the diversity of bat viruses and the factors that determine the emergence of zoonotic viruses from bats.
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, .....
Bats harbour a high viral diversity relative to other mammalian orders; indeed, recent studies have suggested that viral diversity is reflective of the number of species, with Rodentia (rodents) and Chiroptera (bats) containing the most species among mammals8. This viral diversity flags bats as an important taxonomic group for global viral discovery and zoonotic disease surveillance efforts9. These efforts, ultimately aimed at identifying and mitigating future emergence events of bat-borne diseases, have identified thousands of novel bat-derived viral genomic sequences over the past decade. However, as most of these sequences span polymerases and not the surface proteins that often govern cellular entry, little progress has been made towards translating sequence data from novel viruses into a risk-based assessment to quantify zoonotic potential and elicit public health action. Further hampering this effort is an incomplete understanding of the animals themselves, their distributions, behaviours and interactions with the environment, and the processes that lead to contact with humans. In this Review, we discuss the current state and knowledge gaps of bat virus ecology (Box 1) and the molecular barriers to zoonotic disease emergence; we also review advances and challenges in pandemic preparedness and provide a framework for addressing critical deficits in our understanding of bat-borne viruses.
---Our understanding of bat viral ecology has increased substantially over the past two decades, yet this knowledge remains limited to a handful of species and the extremely diverse ecology, biology and life history traits of bats pose a challenge when extrapolating data from any one species or population to bats more broadly. Beyond the within-host processes, including innate immunity and molecular interactions such as receptor compatibility, which can limit susceptibility and viral shedding, ecological factors can facilitate or inhibit virus spillover.
- 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.
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Viral diversity in bats
Research on bat viruses dates back to the 1930s, when Joseph Pawan first identified rabies virus in bats and experimentally infected several different bat species with the virus in Trinidad10,11. The following decades saw a slow accumulation of newly discovered bat viruses12 and an exponential increase after the discovery and isolation of SARS-related coronaviruses (SARSr-CoVs) from bats in 2002 and the concomitant rise of next-generation sequencing technologies13,14. Field research on other bat-borne emerging pathogens, including Nipah virus15–18 and Marburg virus19, in combination with the decreasing cost of next-generation sequencing technologies, spawned the current era of intensive bat viral discovery efforts.
----and filoviruses such as Zaire Ebolavirus24,25 in various bat species. To date, thousands of new bat-associated viral species have been discovered from at least 28 diverse viral families26 (Fig. 1), the vast majority of which are likely host specific with limited zoonotic potential.
For example, astroviruses are hugely diverse and can be found in >30% of individual bats screened27, yet there are no known cases of spillover to humans of the astroviruses found in bats, although this apparent absence may also be due to the lack of active surveillance for these viruses. Other bat-associated viral families, ----
--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.
(RING type zincfinger protein), GeneCards
E3 ubiquitin-protein ligase which promotes ubiquitination of YBX1, leading to its degradation by the proteasome (PubMed:18851979). May play a role as a scaffold protein to promote the assembly of the p53/TP53-MDM2 complex, resulting in increase of MDM2-mediated ubiquitination and degradation of p53/TP53; may function as negative regulator of p53/TP53, leading to both apoptosis and cell growth (By similarity). Regulates DNA-replication and the stability of chromosomal common fragile sites (CFSs) in a ZBTB38- and MCM10-dependent manner. Controls ZBTB38 protein stability and abundance via ubiquitination and proteasomal degradation, and ZBTB38 in turn negatively regulates the expression of MCM10 which plays an important role in DNA-replication (PubMed:24726359). ( RBBP6_HUMAN,Q7Z6E9 )
(Microbial infection) [Isoform 1]: Restricts ebolavirus replication probably by impairing the vp30-NP interaction, and thus viral transcription. (GENECARDS)
---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.
E3 ubiquitin ligase that plays a crucial role in the activation of the IKBKE-dependent branch of the type I interferon signaling pathway (PubMed:24882218, 31694946). In concert with the ubiquitin-conjugating E2 enzyme UBE2K, synthesizes unanchored 'Lys-48'-linked polyubiquitin chains that promote the oligomerization and autophosphorylation of IKBKE leading to stimulation of an antiviral response (PubMed:24882218). Also ubiquitinates MYC and inhibits its transcription activation activity, maintaining the pluripotency of embryonic stem cells (By similarity). Promotes the association of unanchored 'Lys-48'-polyubiquitin chains with DHX16 leading to enhanced RIGI-mediated innate antiviral immune response (PubMed:35263596). ( TRIM6_HUMAN,Q9C030 )
(Microbial infection) Ubiquitinates ebolavirus protein VP35 leading to enhanced viral transcriptase activity. ( TRIM6_HUMAN,Q9C030 )
---Additionally, tetherin123–125 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.
---Large-scale CRISPR–Cas9-mediated knockout (KO)and activation screens in human cells have recently identified specific host factors that are essential to flaviviruses128–130, HIV131, Epstein–Barr virus132 and influenza A virus133,134 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 framework14,63,136
--- 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.
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 GeneXpertTM (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 livestock145–147 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.
----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.
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