Receptor promiscuity in bat sarbecoviruses exposes conserved spike targets

Two studies published in PLOS Biology, together with a Primer accompanying them, converge on a finding that reshapes how scientists think about which bat coronaviruses might pose the greatest threat to people: the sarbecoviruses best equipped to jump between mammalian species are also the ones whose spike proteins carry the most common molecular features, features that human immune systems already recognize from exposure to SARS-CoV-2. The work links the breadth of receptors a virus can bind to the antigenic character of its spike protein, and it identifies conserved regions on that protein that antibodies can target across a wide range of divergent bat viruses.

Coronavirus entry into a cell is initiated by the trimeric, membrane-anchored spike protein. Spike binds a cellular receptor, which for many sarbecoviruses is angiotensin-converting-enzyme 2, or ACE2. The amino acid sequence of ACE2 differs across species, and whether a given spike can bind a particular cell’s ACE2 can determine host range and spillover potential. Understanding how spike protein evolution shapes animal-to-human spread therefore requires working out how the spike–receptor interaction itself evolves. There are evolutionary trade-offs between being a spike protein that can bind many different ACE2 proteins and being one that is species-specific, and exploiting that difference could inform the design of better therapeutics for future coronavirus outbreaks.

Bats harbor a high diversity of coronaviruses, and betacoronaviruses are found in several bat species, making them important natural reservoirs for these viruses. Within that diversity, sarbecoviruses exist on a spectrum from generalists, capable of infecting multiple mammalian host species, to specialists, adapted to narrow host ranges. The two new studies, one immunological and one structural in emphasis, examine how sarbecovirus receptor usage relates to antigenicity and identify conserved spike epitopes that may be exploited for the development of monoclonal antibodies with broad anti-coronavirus efficacy.

The first study, by Thakur and colleagues, investigated how different coronavirus spike–receptor interactions can determine the probability of future spillover from bat sarbecoviruses into humans. The authors found that spike proteins from generalist sarbecoviruses can use many different mammalian ACE2 proteins, and that the generalist spike proteins are phylogenetically and antigenically related to one another. While the ability to cross species can be a fitness advantage for some viruses and increase their potential spread to other mammalian species, the study suggests that this receptor promiscuity comes with an antigenic cost.

That cost was demonstrated directly. Sera from convalescent SARS-CoV-2-infected and vaccinated people bound generalist spike proteins better than they bound specialist spike proteins, because generalist sarbecovirus spikes carry more common epitopes among them—molecular features that human immune systems have already seen in the course of SARS-CoV-2 infection or vaccination. The authors propose that while spillover risk may be increased by sarbecovirus lineages that could spread to humans, the likelihood of such a spillover taking hold is lower, because humans may already have antibodies that bind these spike proteins. The common epitopes in the generalist sarbecovirus spike proteins would, in this scenario, actually limit the virus’s ability to spread in humans due to pre-existing immunity, reducing their true pandemic potential compared with a totally naïve host.

The second study, by Upadhyay and colleagues, turned this same feature of common epitopes to advantage in identifying monoclonal antibodies that bind conserved regions of the spike protein, potentially allowing their use as broadly effective therapeutics. The very receptor generalism that could make clade 1 sarbecoviruses a spillover risk—because they are able to spread to many mammalian hosts—means that the interface of spike to ACE2 has limited structural variability. The sequence variation allowed at that interface is reduced, since the spike must still retain its binding capability to a range of ACE2 proteins. The authors used SARS-CoV-2 convalescent sera to identify antibodies that bind these conserved regions, and they found that monoclonal antibodies targeting these epitopes neutralize a range of divergent bat sarbecoviruses. This provides evidence that the epitopes are evolutionarily constrained, and once identified, they could be used for rational pan-coronavirus vaccine design.

The spike protein is not a rigid structure but a dynamic one; the receptor binding domain can face up or down depending on mutations in the protein sequence and how it interacts with its cognate receptor. Studies have shown that this ability to shift structure translates into how fast the spike protein is cleaved by furin or other host proteases and, ultimately, how efficiently the virus delivers its RNA into cells. During infection, additional host proteins and localized differences in lipids on the plasma membrane can also interact with the virion to determine the speed of the initial spike–receptor binding. The kinetics of a virion binding to its receptor and fusing to the cellular membrane matter because the faster a virion can deposit viral RNA into a cell, the less time antibodies have to bind spike and block virus entry. The immune recognition cost of being a generalist sarbecovirus with common epitopes, as shown by these two studies, is balanced against spike–ACE2 binding affinity, suggesting that many factors are involved in virus spillover and spread in humans.

Both papers are trying to answer a practical question: which bat coronaviruses could realistically jump into people next, and could drugs or vaccines be built and stockpiled before that happens. Thakur and colleagues find that these viruses fall into two broad camps—generalists that can bind to the ACE2 receptor of many different mammals, and specialists that are picky and mostly stay in their own hosts. The generalists turn out to be the close relatives of SARS-CoV-2. They are the viruses most likely to infect humans or pass through an intermediate animal, but because they look similar to SARS-CoV-2, they are also the ones our existing immunity recognizes best. Antibody-based binding of spike drops off sharply for the more distant branches of the family, which means surveillance and countermeasures should not track only the SARS-CoV-2-like viruses.

Upadhyay and colleagues offer a way around that gap. The authors identify a few epitopes on the spike protein that barely change across the whole family, because the virus cannot alter them without losing viral fitness, and they show that antibodies aimed at those spots are able to neutralize both distant bat viruses and the newest SARS-CoV-2 variants. Taken together, the implication is that a pan-sarbecovirus vaccine or stockpiled antibody treatment is a realistic goal if therapeutics can be aimed at the conserved, constrained parts of the spike protein rather than the variable spike surface that current immunity relies on.

Together, the two studies identify a potentially important vulnerability in sarbecovirus pandemic potential: the common epitopes found in a subset of sarbecoviruses that allow these viruses to infect a variety of mammalian species can be used as broad targets for therapeutic design. The mechanism of this conservation is an additional intriguing question that can be used to investigate coronavirus evolution further. After spike–ACE2 binding and entry, other post-entry barriers to viral replication remain, including host innate immunity, interaction with host proteases and other direct protein–protein interactions that impact virus spillover into mammals. These, combined with the spike conservation found in both papers, provide interesting avenues for further research in general coronavirus biology.

Subject of Research: Receptor breadth, antigenic relatedness and conserved spike epitopes in bat sarbecoviruses

Article Title: Conserved spike epitopes persist in generalist bat sarbecoviruses

Article References: Frieman, M. B. (2026). Conserved spike epitopes persist in generalist bat sarbecoviruses. PLOS Biology, 24(10), e3004071. https://doi.org/10.1371/journal.pbio.3004071

Image Credits: AI Generated

DOI: 10.1371/journal.pbio.3004071

Keywords: bat sarbecoviruses, spike protein, ACE2, generalist viruses, conserved epitopes, monoclonal antibodies, SARS-CoV-2, spillover risk, pan-coronavirus vaccine, antigenic relatedness, PLOS Biology, viral evolution