Contextualizing bats as viral reservoirs

Coronavirus disease 2019 (COVID-19) is the latest in a distressing tally of viral infections—including Ebola, Nipah, rabies, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS)—that have evolutionary origins or epidemiological associations with bats. This seeming preponderance of zoonoses has propelled bats from biomedical obscurity to the forefront of global health. Immunological traits have been proposed to allow bats to control viruses differently from other animals. However, incomplete baselines for broader comparisons across vertebrates and extensive immunological variation among bat species casts uncertainty on their distinctiveness as viral reservoirs. Moreover, common perceptions that bats asymptomatically harbor viruses more often than other animals and that their viruses are more diverse or pose systematically heightened zoonotic risk remain unresolved. The search for answers may inspire new approaches to manage disease threats to human and animal health.

Bats (order Chiroptera) comprise ∼1400 species that split from the remaining members of the Scrotifera (carnivores, pangolins, cetaceans, and odd- and even-toed ungulates) over 60 million years ago. The capacity for true flight, specific to bats among mammals, opened diverse trophic niches, making bats key providers of global ecosystem services, including insect pest control, seed dispersal, and pollination of agricultural plants. Flight also introduced physiological challenges that transformed bat life history. For example, aerial transport of young restricts litter sizes to one or two pups annually across most species. The need for multiple bouts of reproduction to maximize fitness therefore favored longevity, hypothesized to be mediated by adaptations to suppress tumors and inflammation caused by DNA damage (1).

Perhaps serendipitously, these mechanisms also limit virus-induced inflammation, potentially explaining why viruses including Marburg virus, SARS-coronavirus (SARS-CoV), and MERS-CoV are thought to cause subclinical infections in the presumed natural bat hosts (Egyptian fruit bats, Rousettus aegyptiacus, for Marburg virus and horse-shoe bats, Rhinolophus spp., for both CoVs) but immunopathology in other vertebrates. Over evolutionary time scales, limited inflammatory responses in bats, together with high population densities and gregarious social behaviors in some species that may facilitate virus transmission, could have selected for viruses that cause severe disease in incidental hosts that lack analogous defenses.

Peculiarities in bat immune systems that plausibly alter viral interactions are increasingly recognized (2). Whether bats are exceptional in this respect is unclear because knowledge of vertebrate immune systems largely derives from inbred mice or immortalized cells, which diverge substantially from wild relatives. Fortunately, the rise in genome sequencing has provided crucial phylogenetic context to the evolutionary origins of bat immunity while facilitating comparisons with diverse nonmodel species (3). For example, comparative transcriptomics showed distinct aspects of innate immunity in little brown bat (Myotis lucifugus) and large flying fox (Pteropus vampyrus) but also in eight other mammalian and avian species (4). By characterizing distinct antiviral features across taxa, efforts to contextualize bat immunity might inspire new strategies to prevent and treat viral zoonoses in humans and animals.

Heightened interest in bat-associated viral zoonoses has also revealed high immunological variation among species. For example, black flying foxes (P. alecto) have an unusually contracted interferon-α (IFN-α) locus (genes that encode components of the innate immune response) and cells that constitutively express IFN-α, inducing antiviral activity (5). However, other bat species have expanded IFN-α loci and lack constitutive IFN-α (6). Similarly, bat species with increased constitutive antiviral defenses may do so through differing gene expression pathways (4), and the antiviral APOBEC gene family has undergone bat lineage–specific expansions or duplication (3). This implies that some of the unusual antiviral defenses in bats arose independently after the evolution of flight. Divergent immunological repertoires among bat species may reflect alternative responses to biogeographic variation in viral assemblages and environmental conditions. Identifying the eco-evolutionary determinants and range of antiviral defenses might help identify unreported reservoirs of zoonoses but requires expanding research beyond the relatively few bat species known to transmit zoonoses.

Whether features of bat immunology predictably translate into functionally distinct antiviral strategies is unresolved. For example, the popular notion that bats tolerate virus infections is supported by experimental infections of bats with Marburg virus, Ebola virus, and MERS-CoV. Conversely, other viruses that may be lethal to humans—including lyssaviruses, Tacaribe virus, and Lloviu virus (human pathogenicity unknown)—are also apparently lethal to bats, including putative reservoir hosts. Sublethal effects of viruses on wild bats are largely undetectable because longitudinal monitoring of individuals is only possible in philopatric species, which live in relatively small groups and can be reliably recaptured. Individual heterogeneities that alter infection outcomes in humans and other animals—such as age, sex, social hierarchies, and past and contemporaneous infections—remain virtually unexplored in bats. Given limited evidence from wild populations, meta-analyses of experimental infections might test whether bats systematically manifest less symptomatic disease than other hosts. Other taxa that are infected with some zoonotic viruses but exhibit mild or no symptoms, such as rodents (for example, Lassa virus) and birds (for example, West Nile virus), provide relevant contrasts.

Whether bat viruses are disproportionately zoonotic is an outstanding global health conundrum. A meta-analysis of 2805 host-virus interactions showed that bats are more likely than other mammals to be infected by viruses that also infect humans (7). Yet when analyses are restricted to hosts that are believed to be important for natural transmission cycles, viral richness among Chiroptera was unexceptional, and they contributed approximately the number of zoonoses expected for the number of species in this order (8). Thus, evolutionarily conserved traits of bats seem unlikely to produce viruses with inflated zoonotic capability. Heightened susceptibility or perhaps surveillance may explain why bats appear to host a relatively large number of zoonotic viruses.

Once introduced into the human population, are bat viruses exceptionally dangerous? One meta-analysis found higher case fatality ratios (CFRs) and lower human-to-human transmissibility of bat viruses; however, the extent that these patterns generalize among bat viruses was uncertain (9). The rabies-causing lyssaviruses, which comprise ∼50% of zoonotic viruses recognized from bats (8), exemplify high CFRs and low transmissibility among humans but, being lethal across all mammals, do not fit the emerging paradigm of tolerance in bats contrasted with virulence in humans. Deviations such as SARS-CoV-2 (low CFR and high transmissibility) and the ebolaviruses (moderate CFR and transmissibility) highlight further complexity.

If the virulence of bat viruses is systematically increased, mathematical models fit to in vitro experiments provide a possible explanation: Accelerated viral propagation with limited cellular morbidity might favor chronic subclinical infections in bats but acute infections in other hosts (10). Although the prediction that bat viruses that cause short-lived, lethal infections in humans infect bats chronically remains unconfirmed in vivo, the short time frames and small sample sizes of most experiments make detecting reactivation of latent viral infections in bats unlikely. Ultimately, virulence is an emergent property of host and virus interactions. As such, determining whether differences among species arise from virus-specific phenomena within bats, inappropriate responses of naïve immune systems, or viral tolerance mechanisms may require profiling immunological responses and within-host dynamics across diverse viruses and host species.

Dimensions of zoonotic emergence

Bat viruses emerge through currently unpredictable interactions of evolutionary and ecological forces. Intrinsic features of bat immune systems have been shaped by bat life history and past viral interactions. Anthropogenic perturbations may alter host-virus interactions at the individual or population levels while breaking down historical barriers between species, culminating in viral emergence.


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Dimensions of zoonotic emergence

Bat viruses emerge through currently unpredictable interactions of evolutionary and ecological forces. Intrinsic features of bat immune systems have been shaped by bat life history and past viral interactions. Anthropogenic perturbations may alter host-virus interactions at the individual or population levels while breaking down historical barriers between species, culminating in viral emergence.


Beyond contextualizing the distinctiveness of bat reservoirs, research should also tackle the real-world complexity underlying viral zoonotic emergence (see the figure). A first step may be to identify how intrinsic traits of bats and extrinsic factors interact to govern viral transmission, community assembly, and zoonotic emergence. For example, spatially replicated metagenomic sequencing in vampire bats (Desmodus rotundus) found no evidence that larger colonies sustain more viruses but revealed elevational gradients and age biases in viral diversity (11). In flying foxes, longitudinal monitoring showed pulsed shedding of multiple paramyxoviruses (a virus family associated with several emerging zoonoses), potentially arising from physiological stress induced by acute food shortages (12). Understanding virus coinfection and community dynamics may also reveal recombination opportunities that potentially enable emergence. Anticipating how anthropogenic perturbations such as land use change, persecution of bats for consumption, trade, or from fear, or misguided efforts at disease control will precipitate emergence is a greater challenge. These actions can alter both viral transmission among bats and the frequency of interspecies contacts (including with intermediate hosts) but are conceptually underdeveloped and rarely tested empirically.

Integrating understanding of the zoonotic process across biomedical, population, and ecosystem scales may enable prevention of zoonotic emergence by reducing virus circulation in bat reservoirs. Knowledge of bat genomics and immunity opens the door for using genetic editing technologies such as CRISPR to engineer viral resistance in wild bats, analogous to ongoing efforts to control Lyme disease in wild mice (13). Historical barriers to delivering vaccines at sufficient scales to alter viral dynamics in wild bat populations are also diminishing. The relative ease of metagenomic sequencing enables rapid discovery of naturally occurring, innocuous, and species-specific bat viruses that might be engineered into transmissible vaccines targeting zoonoses in wild bats. This idea has empirical precedents from efforts to vaccinate wild rabbits against myxomatosis and rabbit hemorrhagic disease (14). The traits expected to facilitate virus transmission in some bats, such as gregariousness and flight, could support live vaccine dissemination, and naturally slow demographic turnover would help to maintain vaccine-induced population-level immunity, allowing less frequent interventions (15). Such potentially transformative strategies require rigorous investigation into efficacy, safety, and ecological impacts as well as overcoming barriers to societal acceptance. Viruses such as rabies virus, Marburg virus, and henipaviruses—for which bat reservoirs are known, host and viral genomes are available, and transmission to humans and/or animals occurs with measurable frequency—can serve as tractable and important models to evaluate and refine candidate interventions.

Viral emergence from bats is largely unpredictable and unpreventable. Solutions require qualitative and quantitative expansions over current practice in bat research, which rarely considers heterogeneities among individuals, populations, and species. This variability can reveal the drivers and phenotypic importance of bat-virus interactions as well as whether they generalize in ways that might aid surveillance or management of zoonotic threats. Given the costs of the COVID-19 pandemic, the need for an ambitious research agenda is more evident now than ever.

Acknowledgments: D.G.S. is funded by a Wellcome Trust Senior Research Fellowship (217221/Z/19/Z). We thank M. Palmarini, S. Babayan, and M. Viana for discussions.

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