Bats are famously deadly vectors for human disease, having been the neighboring source for such famous disease-causing viruses as Ebola, Nipah, SARS, and now SARS-CoV-2. Given that most new human infectious diseases are zoonotic, meaning that they become human diseases by migrating from another animal, one might expect the most important vectors to be farm animals, pets, or pests such as rats, but bats consistently generate far deadlier plagues than these other creatures. The reasons why provide surprising insights into bat biology and also make it clear that studying bats is important epidemiological work.
Bat immune systems are unusually active, fueled by the high metabolic rates bats must maintain to be able to fly. Additionally, most bats are relatively small, meaning they need to spend more energy to maintain their body temperatures against environmental losses, and the high surface area of their wings compounds this effect. High metabolic rates usually come with high incidence of DNA and other damage related to the reactive oxygen species (ROSs) produced during metabolism. This damage results in chronic inflammation and shorter lifespans, and lifespan is positively correlated with body size across numerous animal groups. Because bats are small, warm-blooded, flying animals, one may expect that they would have very short lifespans and frequently experience cancer. But bats instead rarely get cancer and can live for 40 years, compared to the 1 to 5 years of similarly sized rodents. Bats are clearly unusual, and their strangeness helps fuel their status as virus reservoirs.
Cell damage, whether from endogenous ROSs or from invading viruses, does not cause a large-scale inflammatory response in bats the way it does in most other mammals. Instead, bats have overactive interferon-alpha responses, which suppress DNA replication inside damaged cells to slow viral infections and prevent damaged cells from spreading their damage through cellular generations. While bats slow down the progress of infections and repair the damage they cause, they also devote much less of their immune response to directly attempting to destroy viruses than other mammals do. The viruses remain but do the bats comparatively little harm. All disease-causing organisms slowly evolve to become less harmful to their hosts because the alternative is destroying their hosts and then themselves, and bats force that process to proceed much more quickly than has been observed in other animals.
Viruses that evolve to infect bats must contend with all of these systems. Some evolve to hide as non-symptom-causing reservoirs in various tissues in their bat hosts until those hosts are immunosuppressed, such as by stress. Others have intense replication cycles that try to overwhelm bats’ countermeasures, going through rather than around them. The most potentially dangerous bat pathogens do both. When these pathogens encounter other hosts, these same weapons are still present, but now vastly exceed the capacity of the corresponding tools in their new hosts, leading to fast-acting and deadly systemic infections. This is similar to how some venomous snakes have venom capable of rapidly killing animals much, much larger than the snakes themselves—the venom coevolved with their intended prey’s ability to resist it, and it is thereby far less lethal to the intended prey animals than it is to others that didn’t evolve this resistance.
The result is that bats frequently have high loads of viruses that are unusually dangerous to other mammals, making surveying bat populations to get ahead of new viral outbreaks an important and worthwhile endeavor. This is particularly true in developing countries in warm regions, where people are particularly likely to encounter wild bats as new forest land is cleared for agriculture, where biodiversity is particularly high, and where health care systems are usually ill-equipped to respond to an outbreak. Valitutto et al. recently published a study in PLoS One collecting information on coronaviruses resident in bat populations across Myanmar, a country that fits all of these descriptions. They collected oral swabs, rectal swabs and guano samples from free-living bats from three sites and checked them for viral RNA. Sequences detected with qPCR assays were confirmed via Sanger sequencing with the Applied Biosystems 3730 Genetic Analyzer. The team detected three new alpha-coronaviruses, three new beta-coronaviruses, and one previously described alpha-coronavirus, none of which were related to recent zoonotic events such as SARS-CoV, MERS-CoV or SARS-CoV-2, and most of the positives were from guano samples. Their results showed that guano harvesting, a common practice for farmers seeking nutritious fertilizer for their fields, is potentially an important vector for zoonotic transmission of bat coronaviruses.
As Valitutto et al. put it, “currently, active pathogen surveillance at human-wildlife interfaces in Myanmar is limited. Given the potential consequences for public health in light of expanding human activity, continued surveillance for coronaviruses is warranted, especially in other species and human-wildlife interfaces.” It is not currently known whether any of the viruses they discovered in bats have the potential to infect humans or if they could be dangerous, but their mere presence is enough to suggest that paying more attention to wild bat populations may be a way to get ahead of future zoonotic events. A more consistent or complete survey of wild bat viromes will also enable the study of virus spike sequences, which offer insights into their host specificity and may give even clearer warning of future cross-species transmission events.
Guo et al. pursued just such a study. SARS-CoV-2 appears to use angiotensin-converting enzyme 2 (ACE-2) as its entry point, using its viral spike protein to bind to ACE-2. Guo et al. investigated the polymorphism of Chinese horseshoe bat (Rhinolophus sinicus) ACE-2 genes and assessed their associated proteins’ susceptibility and binding affinity for different bat SARS-related coronavirus (SARSr-CoV) spike proteins. As part of their work, samples were analyzed for SARSr-CoV infection by qPCR using the Applied Biosystems AgPath-ID One-Step RT-PCR Reagents and an Applied Biosystems StepOne Real-Time PCR system. R. sinicus ACE-2 is highly variable, with at least eight alleles identified in specimens from across its range, and the different variants show different binding affinities for various SARSr-CoV spike proteins. They also tested human ACE-2 variants and found that all of the SARSr-CoV spike proteins had higher affinity for human variants than any bat variant. All of this suggests that bat ACE-2 genes and proteins are under density-dependent selection, maintaining variation in the population, as viruses evolve to target the most common variants and cyclically decrease their relative fitness. Meanwhile, humans do not have a bat’s immune system and are more susceptible all around. Studies like these can help identify the key protein residues that make a coronavirus most likely to become able to transmit to and between humans, and thus provide clear advance warning of potential disease spread. Similar to the publication from Valitutto et al., this study shows the importance of continued research and surveillance of bats in at-risk areas to potentially predict and prevent the next SARS-like disease emergence.
It is important to note that, despite these infectious disease threats, bats are an indisputably essential component of ecosystems. In addition to their roles as living creatures with niches, they provide valuable ecosystem services in the form of seed dispersal, pollination, guano for fertilizer, and predation of agricultural pests and disease vectors such as mosquitoes. This makes bats undeniable assets to agriculture, especially small-scale farms that have few other options for managing such concerns. This dual status as valuable partners to humans and important natural reservoirs for potential zoonotic pathogens presents a challenge for disease control and requires an informed, multi-pronged response. An important part of that response is well-targeted surveillance of wild bat populations to understand the viruses and other pathogens they carry and the danger they may pose to humans. Such intensive data collection also likely has applications for bat conservation and understanding overall ecosystem health.
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Read the papers
- Valitutto, M.T., et al. (2020) “Detection of novel coronaviruses in bats in Myanmar,” PLoS One 15(4): e0230802.
- Guo, H., et al. (2020) “Evolutionary arms race between virus and host drives genetic diversity in bat SARS-related coronavirus spike genes,” Preprint at bioRxiv (DOI: 10.1101/2020.05.13.093658).
- Cottier, C. (2020) “Why bats are breeding grounds for deadly diseases like Ebola and SARS,” Available at https://www.discovermagazine.com/health/why-bats-are-breeding-grounds-for-deadly-diseases-like-ebola-and-sars (Accessed 16 June 2020).
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