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

Phylogenetic analysis of sarbecoviruses clusters extant sequences into five clades: Ia (including SARS-CoV-1), Ib (including SARS-CoV-2), and clades II-V, with most sequences originating from bats. The usage of the angiotensin-converting enzyme 2 (ACE2) receptor varies across these groups; clade 1 viruses exhibit broad bat ACE2 usage, while clades 3 (e.g., RhGB07) and 5 (e.g., Rc-o319) viruses show more restricted, specialist usage. A novel structure for the RhGB07 Spike helped identify RBD residues linked to this receptor specialism. Generalist phenotypes were observed across a wider range of mammalian ACE2 receptors, including human, non-human primate, livestock, and rodent ACE2, while specialists like RhGB07 showed greater phenotypic diversity in receptor usage. Furthermore, generalist ACE2 users are found to be antigenically related to SARS-CoV-2. This cross-protection is suggested by the fact that specialist viruses still retain some antigenic relatedness to SARS-CoV-2, although with lower neutralisation titres.

The observed correlation between the generalism/specialism of bat ACE2 usage and antigenicity reveals a complex interplay between viral evolution, host receptor availability, and immune response that extends beyond simple sequence homology. The finding that generalist sarbecoviruses are antigenically related to SARS-CoV-2 suggests that broad receptor engagement in bats may predispose these viruses to similar immunologic landscapes, potentially explaining the potential for cross-protection observed with COVID-19 immunity. However, the persistence of antigenic relatedness even among specialists indicates that specific receptor tropism and subsequent evolutionary pressures create divergence that is not entirely erased by shared ancestral traits. This dynamic suggests that ecological drivers—such as the presence of diverse mammalian ACE2 receptors in bat reservoirs—may modulate the evolutionary trajectory, allowing for spillover events to be both facilitated by generalist traits and complicated by specialist adaptations. The shifting tropism observed in SARS-CoV-2 variants underscores the critical need to assess potential reverse zoonotic risks not only from current human hosts but also from evolving reservoir dynamics in biodiverse regions where exposure risk is amplified. Future research must explore whether the spectrum of receptor usage dictates specific cross-neutralisation profiles, and how this mechanism impacts the efficacy of pan-sarbecovirus vaccine strategies across different clades.