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

The study focused on sarbecoviruses, the specific sub-group of coronaviruses that includes both SARS-CoV-1 and SARS-CoV-2. Researchers examined how these viruses interact with angiotensin-converting enzyme 2, or ACE2, the cellular receptor that many coronaviruses utilize to enter host cells. By investigating the ability of various bat coronaviruses to use ACE2 proteins from a broad spectrum of species, the team aimed to understand the host range of these viruses. This host range is a key determinant of spillover risk, as viruses capable of infecting a wide variety of animals are generally considered more likely to jump to humans.

The team analyzed fifteen representative bat coronavirus spike proteins using libraries of ACE2 receptors derived from thirty-four different species. These species included humans, livestock, rodents, and animals previously proposed as intermediate hosts in the transmission chain. The analysis revealed a distinct pattern in receptor usage among the different evolutionary groups of bat sarbecoviruses. Specifically, the researchers identified so-called generalist sarbecoviruses, which can utilize ACE2 receptors from many different species, and found that these were largely confined to the same evolutionary lineage as SARS-CoV-2.

Dr. Nazia Thakur, a postdoctoral scientist at Pirbright and the lead author of the study, explained that the bat coronaviruses currently considered most likely to spill over into humans are also the most likely to be recognized by existing COVID-19 immunity. She noted that while the risk of spillover can never be entirely eliminated, the global exposure to SARS-CoV-2 may have created a more robust immune defense against related viruses. This finding implies that the immune systems of many people are already primed to recognize and neutralize potential future pathogens that share structural similarities with the virus that caused the current pandemic.

The research also highlighted the dynamic nature of viral evolution during the pandemic. The team investigated how the host range of SARS-CoV-2 itself has changed over time. They found that variants, particularly those within the Omicron lineage, acquired specific mutations in the receptor binding domain. These mutations resulted in shifting patterns of ACE2 usage across different animal species, demonstrating that the relationship between viral evolution and host susceptibility is not static but continuously evolving in response to immune pressure and environmental factors.

To assess the practical implications for human health, the scientists examined blood samples from individuals who had recovered from COVID-19. The antibodies present in these samples were tested against a range of bat coronaviruses to measure their neutralizing capacity. The results showed that these antibodies successfully neutralized a variety of closely related bat coronaviruses. This cross-neutralization indicates that the immune response triggered by SARS-CoV-2 is not strictly specific to that single virus but extends to a broader family of related pathogens, providing a layer of protection against potential new infections.

Professor Katie Doores of King’s College London emphasized that the viruses showing the strongest antigenic similarity to SARS-CoV-2 were the most readily recognized and neutralized by the antibodies generated following infection. In contrast, more distantly related bat coronaviruses tended to be specialists, capable of using ACE2 receptors from only a limited range of hosts. However, the researchers also detected lower levels of neutralization against these more distant viruses, suggesting that there is some degree of broader protection even against pathogens that are not closely related to SARS-CoV-2.

Further experiments conducted at both institutions identified several monoclonal antibodies capable of recognizing a remarkably diverse range of sarbecoviruses. The second companion article in the study detailed where these monoclonal antibodies bind on the viral surface, highlighting conserved regions of the coronavirus spike protein. These conserved regions are less likely to mutate without compromising the virus’s ability to infect cells, making them ideal targets for the development of next-generation vaccines and therapeutics. This approach could lead to the creation of pan-sarbecovirus vaccines that offer protection against multiple strains simultaneously.

Dr. Dalan Bailey, head of the Viral Glycoproteins group at Pirbright, described the evidence of cross-neutralization of even some distantly related bat coronaviruses as an encouraging finding. He suggested that this capability points toward the feasibility of developing broadly protective vaccines or therapeutics that can cover a wide spectrum of sarbecoviruses. By targeting conserved epitopes, such interventions could provide a more durable and comprehensive defense against future zoonotic spillover events, reducing the likelihood of a new pandemic emerging from the bat reservoir.

The work underscores the importance of understanding virus host range, receptor usage, and immune recognition in an integrated manner rather than in isolation. By identifying the specific characteristics that distinguish higher-risk viruses from those less likely to spill over into humans, researchers hope to strengthen global pandemic preparedness efforts. This study provides a scientific basis for monitoring specific bat coronavirus lineages and developing targeted interventions that leverage existing immunity to protect against future viral threats, ultimately contributing to a more resilient global health system.

Subject of Research: Cross-immunity between SARS-CoV-2 and bat sarbecoviruses via ACE2 receptor usage

Article Title: COVID-19 immunity may help protect against other bat coronaviruses

Article References: COVID-19 immunity may help protect against other bat coronaviruses. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: SARS-CoV-2, bat coronaviruses, ACE2 receptor, cross-immunity, spillover risk, Pirbright Institute, King's College London, pandemic preparedness, monoclonal antibodies, zoonotic diseases, COVID-19, immunity