ACE2 isoform diversity predicts the host susceptibility of SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the ongoing coronavirus disease 2019 (COVID-19) pandemic. Angiotensin-converting enzyme 2 (ACE2) is the functional receptor for SARS-CoV-2. In our current study, we found that two types of deficient ACE2 isoforms from different mammals compete with full-length ACE2 for association with S protein. One type of ACE2 is a natural soluble isoform, the other type of ACE2 only associates with one loop of the receptor-binding domain (RBD) of the SARS-CoV-2 S protein. Mammals with either type of ACE2 will be deficient in support of SARS-CoV-2 entry. By combining S recognition and isoform analysis of ACE2, we predict that felids, mustelids, hamsters, and sheep are susceptible to SARS-CoV-2, while canids, swines, cattle, and goats are not permissive for SARS-CoV-2. Thus, the differential susceptibilities of mammals with SARS-CoV-2 infection could be partially explained by the ACE2 isoform diversity. Our findings will shed important light on predicting the host range of other zoonotic viruses.