Which mammalian species are at risk of being infected by SARS-CoV-2: an ACE2 perspective

Abstract SARS-CoV-2 can transmit efficiently in humans, but it is less clear what other mammalian are at high risk of being infected. SARS-CoV-2 contain a Spike (S) protein that uses mammalian ACE2 receptors to mediate cell entry, a species with a human-like ACE2 receptor is therefore at risk of being infected by SARS-CoV-2. We compared between 131 mammalian ACE2 genes and 15 coronavirus S proteins. We showed that global similarity reflected by the phylogenetic relationship from ACE2 gene alignment is a poor predictor of high-risk mammals, whereas local ACE2 similarities at key binding sites highlight several high-risk mammals. Both SARS-CoV and SARS-CoV-2 likely have a bat origin; however, direct human transmission is unlikely due to their differences in ACE2 receptors, and various mammals share similar or better homologies in ACE2 receptor with humans. Furthermore, by comparing key binding sites at S protein of SARS-like coronaviruses in high-risk mammals, we found high similarities in S protein binding domains between SARS-CoV-2 and Pangolin-CoV but not Civets-CoV, and high similarities between SARS-CoV and Civets-CoV but not Pangolin-CoV. Hence, evolutionary adaptation of the bat virus in different intermediate hosts could allow it to acquire distinct high binding potential between S protein and human-like ACE2 receptors.