In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 12 ( 2021-12-21), p. e3001510-
Abstract:
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infects a broader range of mammalian species than previously predicted, binding a diversity of angiotensin converting enzyme 2 (ACE2) orthologs despite extensive sequence divergence. Within this sequence degeneracy, we identify a rare sequence combination capable of conferring SARS-CoV-2 resistance. We demonstrate that this sequence was likely unattainable during human evolution due to deleterious effects on ACE2 carboxypeptidase activity, which has vasodilatory and cardioprotective functions in vivo. Across the 25 ACE2 sites implicated in viral binding, we identify 6 amino acid substitutions unique to mouse—one of the only known mammalian species resistant to SARS-CoV-2. Substituting human variants at these positions is sufficient to confer binding of the SARS-CoV-2 S protein to mouse ACE2, facilitating cellular infection. Conversely, substituting mouse variants into either human or dog ACE2 abolishes viral binding, diminishing cellular infection. However, these same substitutions decrease human ACE2 activity by 50% and are predicted as pathogenic, consistent with the extreme rarity of human polymorphisms at these sites. This trade-off can be avoided, however, depending on genetic background; if substituted simultaneously, these same mutations have no deleterious effect on dog ACE2 nor that of the rodent ancestor estimated to exist 70 million years ago. This genetic contingency (epistasis) may have therefore opened the road to resistance for some species, while making humans susceptible to viruses that use these ACE2 surfaces for binding, as does SARS-CoV-2.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001510
DOI:
10.1371/journal.pbio.3001510.g001
DOI:
10.1371/journal.pbio.3001510.g002
DOI:
10.1371/journal.pbio.3001510.g003
DOI:
10.1371/journal.pbio.3001510.g004
DOI:
10.1371/journal.pbio.3001510.s001
DOI:
10.1371/journal.pbio.3001510.s002
DOI:
10.1371/journal.pbio.3001510.s003
DOI:
10.1371/journal.pbio.3001510.s004
DOI:
10.1371/journal.pbio.3001510.s005
DOI:
10.1371/journal.pbio.3001510.s006
DOI:
10.1371/journal.pbio.3001510.s007
DOI:
10.1371/journal.pbio.3001510.s008
DOI:
10.1371/journal.pbio.3001510.s009
DOI:
10.1371/journal.pbio.3001510.s010
DOI:
10.1371/journal.pbio.3001510.s011
DOI:
10.1371/journal.pbio.3001510.s012
DOI:
10.1371/journal.pbio.3001510.s013
DOI:
10.1371/journal.pbio.3001510.s014
DOI:
10.1371/journal.pbio.3001510.s015
DOI:
10.1371/journal.pbio.3001510.s016
DOI:
10.1371/journal.pbio.3001510.s017
DOI:
10.1371/journal.pbio.3001510.s018
DOI:
10.1371/journal.pbio.3001510.r001
DOI:
10.1371/journal.pbio.3001510.r002
DOI:
10.1371/journal.pbio.3001510.r003
DOI:
10.1371/journal.pbio.3001510.r004
DOI:
10.1371/journal.pbio.3001510.r005
DOI:
10.1371/journal.pbio.3001510.r006
DOI:
10.1371/journal.pbio.3001510.r007
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2126773-X
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