Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates

Abstract

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.

SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals

“…As shown in previous studies, and supported by experimental data, many primates are predicted to be at high risk 19,41,42 . In agricultural settings, camels, cows, sheep, goats and horses also have relatively low ΔΔG values, suggesting comparable binding affinities to humans, in agreement with experimental data 20,21,48 .…”

“…However, to our knowledge there have been few studies of relative changes in the energies of the S-protein:ACE2 complex 43 . A number of recent studies 20,21,42 have suggested that, due to high conservation of ACE2, some animals are vulnerable to infection by SARS-CoV-2. Concerningly, these animals could, in theory, serve as reservoirs of the virus, increasing the risk of future zoonotic events, though transmission rates across species are currently not known.…”

“…Most studies simply considered the number of residues mutated relative to human ACE2 32,57−59 , although some also analyse the effect that these mutations have on the interface stability 34,41,59,60 . The most comprehensive of these studies analysed the number and locations of mutated residues in ACE2 orthologues from 410 species 42 , but did not perform detailed energy calculations as we have done. Few studies have explored changes in the energy of the S-protein:ACE2 complex on a large scale.…”

Predicting susceptibility to SARS‐CoV‐2 infection based on structural differences in ACE2 across species

“…Prior studies of ACE2 sequence alignment with limited structural modeling have suggested that pigs are susceptible to infection, 52 and that hamsters and house cats are in an intermediate-risk group. 53 Recent experimental work with direct inoculation, however, has demonstrated that pigs are non-susceptible, 7 and that house cats and Golden Syrian hamsters are susceptible. 5,7 We identified key residues on which to build a susceptibility score that closely matches experimentally verified in vivo susceptibility, including predicting an intermediate susceptibility of the pig and higher susceptibility of house cats and Golden Syrian hamsters.…”

Coronavirus Infection of the Central Nervous System: Animal Models in the Time of COVID-19

“…Recent data relating to treatment of both non-CNS and CNS FIP with antiviral drugs may have relevance to specific aspects of ongoing trials in SARS-CoV-2 patients. Interestingly, domestic and big cats are susceptible to SARS-CoV-2 infection, consistent with expression of ACE2 viral receptor in these species (87,88), although associated clinical CNS disease has not been reported (89,90).…”