Comparative ACE2 variation and primate COVID-19 risk

Abstract

The emergence of SARS-CoV-2 has caused over a million human deaths and massive global disruption. The viral infection may also represent a threat to our closest living relatives, nonhuman primates. The contact surface of the host cell receptor, ACE2, displays amino acid residues that are critical for virus recognition, and variations at these critical residues modulate infection susceptibility. Infection studies have shown that some primate species develop COVID-19-like symptoms; however, the susceptibility of most primates is unknown. Here, we show that all apes and African and Asian monkeys (catarrhines), exhibit the same set of twelve key amino acid residues as human ACE2. Monkeys in the Americas, and some tarsiers, lemurs and lorisoids, differ at critical contact residues, and protein modeling predicts that these differences should greatly reduce SARS-CoV-2 binding affinity. Other lemurs are predicted to be closer to catarrhines in their susceptibility. Our study suggests that apes and African and Asian monkeys, and some lemurs, are likely to be highly susceptible to SARS-CoV-2. Urgent actions have been undertaken to limit the exposure of great apes to humans, and similar efforts may be necessary for many other primate species.

Fig. 1. ACE2 protein sequence alignment and evolutionary relationships of study species.

Branch lengths represent the evolutionary distance (time, in millions of years) estimated from TimeTree. We outline amino acid residues at critical binding sites for the SARS-CoV-2 spike receptor-binding domain. Solid outlines highlight sites predicted to have the most substantial impact on viral binding affinity. Notably, protein sequences of catarrhine primates are highly conserved, including uniformity among amino acids at all binding sites. Primate species that are able to be successfully infected with COVID-19 are indicated in red. Predicted susceptibility to COVID-19 for other primates is additionally coded by terminal branch colors. We use the nomenclature Cebus capucinus to be consistent with the species name used in the genome annotation but note the recent adoption of Cebus imitator for this species. Silhouettes are from PhyloPic.org and available under the Public Domain Dedication 1.0 license, with the exception of Cebus (Sarah Werning; Creative Commons Attribution 3.0 Unported).

Fig. 2. Model of human ACE2 in complex with SARS-CoV-2 RBD.

Key ACE2 interfacial residues are highlighted (a). Interactions at critical binding sites 41 and 42 are shown for the residues found in all catarrhines (apes and monkeys in Africa and Asia) (b), and for the residues found in all platyrrhines (monkeys in the Americas) (c). The dashed lines indicate predicted hydrogen bonding interactions. Y41 participates in extensive van der Waals and hydrogen bonding interactions with RBD; these interactions are abrogated with histidine. Q42 side-chain amide serves as a hydrogen acceptor and donor to contact RBD; change to glutamic acid diminishes the hydrogen bonding interactions.