Structural basis of increased binding affinities of spikes from SARS-CoV-2 Omicron variants to rabbit and hare ACE2s reveals the expanding host tendency.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has swept the globe and caused immense health and economic damage. SARS-CoV-2 has demonstrated a broad host range, indicating a high risk of interspecies transmission and adaptive mutation. Therefore, constant monitoring for potential hosts is of immense importance. In this study, we found that Omicron BA.4/5 and subsequent-emerged sub-variants exhibited enhanced binding to both rabbit and hare angiotensin-converting enzyme 2 (ACE2), and we elucidated the structural mechanism of their recognition. From the structure, we found that Q34, a unique residue of rabbit ACE2 compared to other ACE2 orthologs, plays an important role in ACE2 recognition. These results address the probability of rabbits/hares being potential hosts of SARS-CoV-2 and broaden our knowledge regarding the molecular mechanism of SARS-CoV-2 interspecies transmission.