Comparative ACE2 variation and primate COVID-19 risk

Abstract

The emergence of the novel coronavirus SARS-CoV-2, which in humans is highly infectious and leads to the potentially fatal disease COVID-19, has caused tens of thousands of deaths and huge global disruption. The viral infection may also represent an existential threat to our closest living relatives, the nonhuman primates, many of which have already been reduced to small and endangered populations. The virus engages the host cell receptor, angiotensin-converting enzyme-2 (ACE2), through the receptor binding domain (RBD) on the spike protein. The contact surface of ACE2 displays amino acid residues that are critical for virus recognition, and variations at these critical residues are likely to modulate infection susceptibility across species. While infection studies have shown that rhesus macaques exposed to the virus develop COVID-19-like symptoms, the susceptibility of other nonhuman primates is unknown. Here, we show that all apes, including chimpanzees, bonobos, gorillas, and orangutans, and all 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 significant contact residues, and protein modeling predicts that these differences should greatly reduce the binding affinity of the ACE2 for the virus, hence moderating their susceptibility for infection. Other lemurs are predicted to be closer to catarrhines in their susceptibility. Our study suggests that apes and African and Asian monkeys, as well as some lemurs are all likely to be highly susceptible to SARS-CoV-2, representing a critical threat to their survival. Urgent actions may be necessary to limit their exposure to humans.

Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates

“…Several recent studies examined the role of ACE2 in SARS-CoV-2 binding and cellular infection, and its relationship to experimental and natural infections in different species (30,(41)(42)(43)(44)(45)(46) . Our study design differs substantially from those studies in several aspects: 1) we analyzed a larger number of primates, carnivores, rodents, cetartiodactyls and other mammalian orders, and an extensive phylogenetic sampling of fishes, birds, amphibians and reptiles; 2) we analyzed the full complement of S-binding residues across the ACE2 binding site, which was based on a consensus set from two independent studies (13, 21) ; 3) we used different methodologies to assess ACE2 binding capacity for SARS-CoV-2 S;…”

ACE2 and TMPRSS2 variation in savanna monkeys (Chlorocebus spp.): Potential risk for zoonotic/anthroponotic transmission of SARS-CoV-2 and a potential model for functional studies

“…However, receptor usage provides an indication of species that could potentially be susceptible [11] [14]. The close proximity of humans and wild non-human primates provides potential for crossspecies transmission of pathogens, and for some endangered species this could have devastating effects [14]. Similarly, identifying if non-human primates have the potential to act as intermediates hosts, as for Ebola virus [49], would be important for understanding zoonotic transmission and use of animal models.…”

“…Finally, we used SSIPe [61] to assess the change in protein binding affinity caused by the discovered Asp30Gly mutation at the critical residue identified via alanine scanning mutagenesis analyses performed by Melin et al [14]. The change in free energy due to the mutation was inferred by comparing against a reference interaction of human ACE2 receptor bound to the SARS-CoV-2 spike receptor binding domain (PBD 6M0J).…”

“…has not yet been investigated. This is cause for great concern, not just from a global and community health perspective, but also from a conservation perspective, as many critically endangered nonhuman primates may also be vulnerable to COVID-19 [14].…”

“…Only one of the missense-mediated changes in amino acid residues, also in Ch. sabaeus (X:14,077,550; Asp30Gly), involves a conversion at one of the critical binding sites for SARS-CoV-2 identified by Melin et al[14]. This substitution is predicted to destabilize the binding of SARS-CoV-2 to ACE2 receptors (ΔΔG bind = 0.958 kcal/mol), and of all the point mutations analyzed in a recent survey of primates[14], Asp30Gly reduces the predicted binding affinity more than all but the Tyr21His variant, which is found in most strepsirrhines (lemurs and lorisoids) and all platyrrhines (monkeys from the Americas) considered.Savanna monkeys in the extended pedigree of Caribbean-origin Ch.…”