The evolving landscape of sarbecovirus ACE2 binding

From the Bloom lab, Basic Sciences and Public Health Sciences Divisions

For the past two years, Dr. Jesse Bloom, Professor in Fred Hutch’s Basic Sciences and Public Health Sciences Divisions, and postdoctoral fellow Dr. Tyler Starr have engaged in a high-stakes race against the rapidly evolving SARS-CoV-2 virus. Their aim: to understand how the virus’s ever-changing genetic sequence affects its ability to cause disease and to evade our attempts to fight it off. While they remain engaged in this arms race, Drs. Bloom and Starr have also set their sights on a broader goal: anticipating and preparing for the next potential pandemic. Their interest in this topic stems from an appreciation of SARS-CoV-2’s own path to pandemicity – as a historically bat-infecting virus that evolved to infect human hosts – and a recognition that there exists a whole world of viruses waiting to make similar leaps to humans. In fact, SARS-CoV-2 is the second in a clade of coronaviruses known as the sarbecoviruses to have recently made such a leap. Just two decades ago, the SARS-CoV-1 virus caused the even more lethal SARS outbreak that very nearly also led to global catastrophe. What caused these sudden outbreaks? “Although human infectivity depends on many factors, the ability to bind to human receptors is certainly a key factor”, write Drs. Bloom and Starr. And in the case of both SARS-CoV-1 and SARS-CoV-2, the human receptor that is key to their infectivity is ACE2. In a new article published in Nature, their group collaborated with Dr. David Veesler’s lab at the University of Washington to more broadly examine the ability of sarbecoviruses to bind ACE2, the evolutionary history of this interaction, and the potential for additional leaps across species boundaries.

Binding of the sarbecovirus receptor-binding domain (RBD) to ACE2 “has been observed only sporadically among the broader diversity of bat sarbecoviruses,” the authors explain. Furthermore, ACE2 binding had previously only been observed in a subset of sarbecoviruses found in Asia, but not those from Africa or Europe. The first question that intrigued the group, therefore, was “whether ACE2 binding is an ancestral trait of sarbecovirus RBDs that has been lost in some RBD lineages, or a trait that was acquired more recently in a subset of Asian sarbecovirus RBDs.” To answer this question, the authors traced the evolutionary history of ACE2 binding by measuring the binding characteristics of 45 sarbecoviruses from around the world. To do so, they expressed the RBDs of these viruses on the surface of yeast cells and determined their binding affinities for the ACE2 proteins of several mammals, including bats and humans. As expected, the group observed ACE2 binding in limited subsets of sarbecoviruses, primarily in the Asian subgroups containing SARS-CoV-1 and SARS-CoV-2. Surprisingly, however, they also observed ACE2 binding in viruses from Africa and Europe, suggesting this property is not as geographically restricted as previously believed. The authors also reconstructed the likely sequences of ancestral RBDs and found them capable of binding ACE2, suggesting that ACE2 binding was once a more ubiquitous property of sarbecoviruses but has been lost in some lineages.

sarbecovirus phylogeny
(Left) Sarbecovirus phylogeny color coded by clade. (Right) Sarbecovirus binding to the ACE2 receptors of several mammalian species. Image provided by Dr. Tyler Starr

Next, the authors asked if all sarbecovirus RBDs used to bind ACE2, how easily could the viruses that have since lost this ability regain it through mutation? And, for those RBDs that still can bind non-human ACE2, how easily could they gain the ability to bind human ACE2? To answer this, they generated and tested mutant libraries for 14 RBDs and found, unfortunately, that the answer is quite easily. They identified individual mutations in all of these viruses that allowed them to either regain the ability to bind ACE2 of at least one species, gain the ability to expand their ACE2 binding to a new species (including human), or bind ACE2 with enhanced affinity. “The results show that ACE2 binding is a remarkably evolvable trait,” the group concludes.

This work highlights the growing concern that additional spillover events, in which new sarbecoviruses mutate to infect humans and cause disease outbreaks, are very possible in the future, and demonstrates the need to track the evolution of this group of viruses. Dr. Starr also points out the importance of their discovery of ACE2 binding in African and European sarbecoviruses on our pandemic preparedness efforts. “Although [sarbecoviruses] are found across Asia, Africa, and Europe, up until 2020, the viruses that were thought to pose any possibility of future spillover were thought to be geographically and evolutionarily restricted to a particular lineage of these viruses that had only been found in a single province in Southern China. Many groups are working to develop tools for future pandemic preparedness. The goal of these tools is to develop vaccines or antibody therapeutics that have a breadth of protection against the entire diversity of viruses in this family that might pose concern for future spillovers…Our results suggest that there could be many more, undescribed lineages across Asia, Europe, or Africa, for which pandemic potential is possible though unknown. It would be wise for these pre-emptive tools to encompass this broader diversity now, rather than after some other virus spills over from somewhere new on the evolutionary tree, just as SARS-CoV-2 did in 2020.”

This work was supported by the National Institutes of Health, the Pew Charitable Trusts, the Burroughs Wellcome Fund, Fast Grants, the Bill and Melinda Gates Foundation, the Russian Foundation for Basic Research, the Damon Runyon Cancer Research Foundation, and the Howard Hughes Medical Institute.

Starr TN, Zepeda SK, Walls AC, Greaney AJ, Alkhovsky S, Veesler D, Bloom JD. ACE2 binding is an ancestral and evolvable trait of sarbecoviruses. Nature. 2022 Mar;603(7903):913-918. doi: 10.1038/s41586-022-04464-z. Epub 2022 Feb 3. PMID: 35114688; PMCID: PMC8967715.