Cross-species recognition of bat coronavirus RsYN04 and the cross-reaction of SARS-CoV-2 antibodies against the virus

Since the outbreak of COVID-19, many SARS-CoV-2-related coronaviruses (CoVs) have been discovered. Previous research identified a novel lineage of SARS-CoV-2-related CoVs in bat, such as RsYN04, which recognizes human angiotensin-converting enzyme 2 (ACE2) and poses a potential threat to humans. Here, we screened the binding of RsYN04 receptor-binding domain (RBD) to ACE2 orthologs from 52 animal species, and found that the virus shows a narrower ACE2-binding spectrum than SARS-CoV-2. However, the T484W mutation in the RBD can broaden the spectrum. We also evaluated 44 SARS-CoV-2 antibodies targeting seven epitope communities in RBD, together with the sera from COVID-19 convalescents and vaccinees, for their cross-reaction against RsYN04. Our results showed that all the antibodies, except for RBD-6 and RBD-7 classes, did not bind to RsYN04 RBD, indicating the substantial immune difference from SARS-CoV-2. Furthermore, the complex structure of the RsYN04 RBD with a cross-reactive antibody S43 in RBD-7 revealed a potently broad epitope for the development of therapeutics and vaccines. Our findings suggest RsYN04 and other viruses belonging to the same clade have the potential to infect several species including humans, highlighting the necessity for viral surveillance and development of broad anti-coronavirus countermeasures.