The viruses that gave rise to SARS-CoV-2 have been circulating in horseshoe bats and related mammals across Asia for millennia, and most of them have never spilled over into people. Yet a small number of these bat sarbecoviruses clearly can infect humans, as the COVID-19 pandemic demonstrated. A central question for pandemic preparedness has therefore been whether scientists can look at the properties of a newly discovered bat coronavirus and make an evidence-based judgement about how dangerous it might be. A new study published in PLOS Biology suggests that one measurable property, the breadth of species whose ACE2 receptor a virus can use, may be a surprisingly informative signal, predicting not only which animals a virus can infect but also how closely related it is to SARS-CoV-2 in the eyes of the human immune system.

Sarbecoviruses, the subgenus of coronaviruses that includes SARS-CoV and SARS-CoV-2, attach to their host cells through the receptor-binding domain, or RBD, of the Spike protein. This domain grips the angiotensin-converting enzyme 2 receptor, ACE2, on the surface of host cells, and it is also the principal target of neutralising antibodies. That dual role creates an intimate link between host range and antigenicity: the same molecular surface that determines which species’ receptors a virus can engage also determines how well antibodies raised against one virus recognise another. The research team, led by scientists at The Pirbright Institute together with collaborators including researchers at King’s College London, set out to map that relationship systematically across a diverse collection of bat sarbecoviruses.

The experimental strategy combined three complementary approaches. First, the researchers used binding assays to test whether the Spike proteins of different sarbecoviruses could attach to ACE2 proteins from a wide panel of mammalian species. Second, they used pseudotype-entry assays, in which harmless lentiviral particles are decorated with each coronavirus Spike protein, to test whether receptor binding actually translates into cell entry. Third, they measured how sera from SARS-CoV-2 convalescent individuals and monoclonal antibodies from vaccinated people who had experienced breakthrough infections neutralised the different viruses. By running the same viruses through all three assays, the team could directly correlate receptor usage with antigenic behaviour.

The results revealed a striking pattern. Sarbecoviruses in clade 1, the group that contains SARS-CoV-2 itself and the BANAL viruses isolated from bats in Laos, tended to be generalists. Their Spike proteins could productively engage ACE2 receptors from many different bat species, indicating that they are not finely tuned to a single host. In contrast, viruses from clade 3, exemplified by RhGB07, and clade 5, exemplified by Rc-o319, behaved as specialists, using a much narrower range of ACE2 receptors. Rc-o319, which was previously known to be unable to use human ACE2 efficiently, fits this specialist profile, whereas the BANAL viruses, which can use human ACE2, sit firmly in the generalist camp alongside SARS-CoV-2.

To understand the structural basis of this specialism, the team solved a novel structure of the RhGB07 Spike protein. The structure allowed them to identify specific residues within the RBD that are associated with the restricted receptor usage of this clade 3 virus. These residues presumably shape the receptor-binding interface in ways that favour particular bat ACE2 variants while excluding others. Such structural insights are valuable because they point to the molecular features that distinguish viruses capable of flexible receptor engagement from those locked into narrow host ranges, and they may help predict the properties of newly discovered sarbecoviruses from sequence data alone.

When the researchers extended their receptor panel beyond bats to include more diverse mammalian ACE2 proteins, the generalist phenotype largely held. Clade 1 viruses could bind and enter cells expressing ACE2 from humans, non-human primates, livestock, and rodents, as well as from species considered potential intermediate reservoir hosts, such as civets, raccoon dogs, and pangolins. This is significant because intermediate hosts are thought to have played a role in previous coronavirus spillovers, including the emergence of SARS-CoV in 2002. A virus that can already use the receptors of many species faces fewer barriers on the path from bat to human. The specialist viruses, by contrast, showed wider phenotypic diversity across this expanded panel, with RhGB07 exhibiting a more idiosyncratic pattern of receptor usage that did not simply mirror its bat-host profile.

The study also examined how SARS-CoV-2’s ongoing evolution in humans has changed its receptor preferences. Comparing variants that have emerged during the pandemic, the researchers found an expanding and, in some cases, shifting pattern of generalism, particularly for Omicron and its many sub-lineages. Omicron’s Spike has accumulated numerous mutations in the RBD, and these changes appear to have broadened or reconfigured the range of ACE2 molecules the virus can engage. This observation underscores that receptor usage is not a fixed property of a virus but a dynamic trait that can evolve under immune pressure and changing transmission landscapes, with potential consequences for which animal species might serve as new reservoirs for human-derived variants.

The antigenic side of the analysis produced equally important findings. When convalescent sera from people who had recovered from COVID-19 were tested against the panel of bat sarbecoviruses, clade 1 viruses, being phylogenetically closest to SARS-CoV-2, were antigenically the most similar. There was robust evidence for cross-neutralisation of these viruses, meaning that immunity generated against SARS-CoV-2 offers meaningful protection against its closest bat relatives. Importantly, however, the team also found evidence for limited cross-neutralisation across the entire subgenus, suggesting that even the more distantly related specialist viruses are not completely invisible to immunity primed by SARS-CoV-2 infection. This graded pattern of cross-reactivity maps closely onto the phylogenetic and receptor-usage relationships the researchers had established.

Using monoclonal antibodies derived from COVID-19 vaccinees who subsequently experienced breakthrough infections, the researchers were able to pinpoint which classes of antibody epitopes are responsible for the broader neutralisation observed across the sarbecovirus panel. Because antibodies recognise specific structural features of the RBD, identifying the epitope classes that mediate cross-neutralisation provides a rational basis for designing vaccines and therapeutics with deliberately broad coverage. Antibodies directed against more conserved features of the receptor-binding interface, rather than those specific to SARS-CoV-2’s particular configuration, appear to underpin the wider neutralising activity.

Taken together, the study delivers a unifying message: generalist ACE2 usage, phylogenetic proximity to SARS-CoV-2, and antigenic similarity travel together. A bat sarbecovirus that can flexibly use receptors from many mammalian species is likely to be a close relative of SARS-CoV-2 and likely to be partially neutralised by existing human immunity. This constellation of traits offers surveillance teams a practical framework for triage. When a new sarbecovirus is discovered, characterising its receptor-binding breadth through binding and pseudotype assays could provide an early, laboratory-based assessment of both its zoonotic potential and the degree to which current vaccines and antibodies might protect against it. As bat habitats are disturbed and human-wildlife interfaces expand, such tools for distinguishing the generalists from the specialists among the thousands of circulating bat coronaviruses could prove essential for anticipating, and perhaps preventing, the next spillover.

Subject of Research: ACE2 receptor usage breadth as a predictor of host range and antigenic relatedness across bat sarbecoviruses

Article Title: Breadth of ACE2 receptor usage predicts host range and antigenic relatedness across bat sarbecoviruses

Article References: Thakur, N., Newman, J., Ni, D., Seow, J., Hay, A. L., Lee, Y., Upadhyay, A., Ekundayo, B. E., Hammond, J. A., Peacock, T. P., Lau, K., Doores, K. J., & Bailey, D. (2026). Breadth of ACE2 receptor usage predicts host range and antigenic relatedness across bat sarbecoviruses. PLOS Biology, 24(10), e3003944. https://doi.org/10.1371/journal.pbio.3003944

Image Credits: AI Generated

DOI: 10.1371/journal.pbio.3003944

Keywords: sarbecoviruses, ACE2, SARS-CoV-2, host range, receptor-binding domain, antigenicity, cross-neutralisation, bat coronaviruses, zoonotic spillover, Omicron, monoclonal antibodies, pseudotype assays

Bats’ remarkable ability to withstand decades of strenuous flight while keeping infections, inflammation, and cancer in check may offer new clues to healthier human aging Bats are unusually long-lived for animals of their size. Small mammals generally burn energy quickly and die relatively young, yet some bats survive for several decades. Brandt’s myotis, Myotis brandtii, [...]

Bat DNA may hold clues to a long and healthy life, according to an international team of researchers.

These small creatures grace the night skies with extremely long lifespans and low cancer rates—traits that may ultimately benefit humanity if scientists can figure out how bats achieve them. Now, in a recent paper published in Nature, scientists from the University of Vermont and Penn State University led an international team investigating bats’ immune systems.

The paper’s crucial discovery was that bat DNA reveals the creatures encode genomic changes to handle exposure to environmental pathogens.

The Miraculous Bat

“Pathogen adaptation, longevity, and cancer resistance—they are fundamentally linked,” explained co-lead author Elise Lauterbur, an assistant professor of evolutionary biology at the University of Vermont. “Many of the genes that have adapted to viruses in bats are genes that are also involved in longevity and cancer resistance.”

Bats make an ideal study subject as they are only second to rodents in diversity, allowing scientists to study a wide variety of features in a single order.

“If you look at two bats, the same size, one lives 3 years the other lives 30 years and they are very closely related, like humans and Neanderthals, you can essentially find a very small number of genetic changes that leads to a very big change in their lifespan,” said co-lead author Juan Manuel “Manny” Vazquez, an assistant professor at Penn State University. “And that is kind of the Holy Grail for evolutionary medicine.”

The work focused on Myotis, one of the largest bat genera, whose members are found across much of the globe outside Antarctica. Eight Myotis species came under the microscope, with the team experimenting on cultured cells and analyzing their genomes. Among the species sampled were little brown bats (Myotis lucifugus), known both for their long lifespans, even among bats, and their susceptibility to the deadly white-nose syndrome, a fungal disease.

Even the researchers’ sample-collection methods were novel. They developed a technique akin to ear-piercing to collect small tissue samples from bat wings, which were then used to establish cell cultures. The team says this both spared the animals’ lives and produced more scientifically useful samples.

Bat Evolution

In their detailed examination, the researchers identified evidence of past events in which Myotis bats encountered pathogens and how adaptations to those viruses were selected for during their evolution.

Their work identified specific genomic changes, including the duplication or deletion of genes, associated with adaptation to environmental pathogens. This illuminated important differences in bats’ responses to DNA and RNA viruses compared with humans and other primates, potentially contributing to bats’ long, healthy lifespans.

Comparatively, human evolution shows stronger selection involving proteins that interact with RNA viruses like influenza, while bats show stronger selection involving proteins that interact with DNA viruses such as herpesviruses. These differences may help explain the distinct ways bats and primates have adapted to viral threats.

Cancer Resistance

The team also identified genetic mechanisms that could help explain bats’ resistance to cancer and other age-related diseases. In some cases, duplicated genes can diversify their functions, allowing different copies to perform distinct roles. According to the researchers, this may provide immune advantages that help bats combat multiple viruses while also contributing to pathways associated with longevity.

Another important finding was that while most mammals contain one copy of the immune-related gene PRKN, some bat species contain two or even three copies, suggesting that additional copies may offer evolutionary advantages. The team says this could provide important insights for future cancer research, given bats’ unusual ability to repair or eliminate damaged cells.

The research doesn’t point to immediate treatments for humans, but it does provide starting points for reconsidering human illness in the context of bat immunology and evolution.

“Everything is connected,” Vazquez concluded. “Everything uses the same shared set of biology. … We don’t have to treat all of these different problems as silos. We can now start focusing on systems like bats to understand how we can solve multiple human age-related diseases.”

The paper, “Insights into Longevity and Virus-Driven Adaptation from Myotis Bat Genomes,” appeared in Nature on August 26, 2026.

Ryan Whalen covers science and technology for The Debrief. He holds an MA in History and a Master of Library and Information Science with a certificate in Data Science. He can be contacted at ryan@thedebrief.org, and follow him on Twitter @mdntwvlf.