Predicting mammalian species at risk of being infected by SARS-CoV-2 from an ACE2 perspective

Abstract

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.

Yeast surface display-based identification of ACE2 mutations that modulate SARS-CoV-2 spike binding across multiple mammalian species

“…It is reasonable to posit that Leu to Ile substitution decreases the free energy of the hydrophobic interaction between the Phe486 aromatic ring and the cognate interacting ACE2 amino acid sidechain. The imidazole group sidechain of Human ACE2 residue His34 is in direct contact with the sidechains of spike RBD residues Leu455 and Gln493; given the substantial level of primary sequence conservation across mammalian ACE2s [9,13] it is plausible that contacts between ACE2 residue 34 and one or more spike RBD sidechains exist in the context of many or all of these orthologs. This may explain why high affinity ACE2 clones identified from the cat, dog, and pig libraries carried substitutions at position 34.…”

SARS-CoV-2 vaccine for domestic and captive animals: An effort to counter COVID-19 pandemic at the human-animal interface

“…Therefore, it is necessary to perform in-depth investigations to explore the interrelationships between animals and humans for disease transmission, spread, and adopt appropriate prevention and control strategies following interdisciplinary and holistic approaches [13] , [14] , [15] , [16] , [17] , [18] . In addition, the key binding sites on the human ACE2 receptor are most conserved in the primates (especially Cercopithecoidae and Hominidae families) [19] . Furthermore, the ACE2 sites are highly conserved in some species belonging to Carnivora, Lagomorpha, Proboscidea, Artiodactyla, Chiroptera, Rodentia, Sirenia, and Perissodactyla orders indicating a potential for spillover SARS-CoV-2 infection from humans [19] .…”

“…In addition, the key binding sites on the human ACE2 receptor are most conserved in the primates (especially Cercopithecoidae and Hominidae families) [19] . Furthermore, the ACE2 sites are highly conserved in some species belonging to Carnivora, Lagomorpha, Proboscidea, Artiodactyla, Chiroptera, Rodentia, Sirenia, and Perissodactyla orders indicating a potential for spillover SARS-CoV-2 infection from humans [19] .…”

Post-Alignment Adjustment and Its Automation

“…I illustrate two such cases. The first involves aligned sequences (Figure 1) taken from a study of mammalian ACE2 sequences in an effort to predict which mammalian species might be susceptible to SARS-CoV-2 infection [14]. The sequences were aligned with MAFFT with all optimization options selected.…”