SARS-CoV-2 can transmit efficiently in humans, but it is less clear which other mammals are at risk of being infected. SARS-CoV-2 encodes a Spike (S) protein that binds to human ACE2 receptor to mediate cell entry. A species with a human-like ACE2 receptor could therefore be at risk of being infected by SARS-CoV-2. We compared between 132 mammalian ACE2 genes and between 17 coronavirus S proteins. We showed that while global similarities reflected by whole ACE2 gene alignments are poor predictors of high-risk mammals, local similarities at key S protein-binding sites highlight several high-risk mammals that share good ACE2 homology with human. Bats are likely reservoirs of SARS-CoV-2, but there are other high-risk mammals that share better ACE2 homologies with human. Both SARS-CoV-2 and SARS-CoV are closely related to bat coronavirus. Yet, among host-specific coronaviruses infecting high-risk mammals, key ACE2-binding sites on S proteins share highest similarities between SARS-CoV-2 and Pangolin-CoV and between SARS-CoV and Civet-CoV. These results suggest that direct coronavirus transmission from bat to human is unlikely, and that rapid adaptation of a bat SARS-like coronavirus in different high-risk intermediate hosts could have allowed it to acquire distinct high binding potential between S protein and human-like ACE2 receptors.

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.

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