Evolutionary pathways to SARS-CoV-2 resistance are opened and closed by epistasis acting on ACE2

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 immune 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.

Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics

“…Long-ranged interactions between different sites within a given protein is critically important for protein function (Peters and Lively 1999; Bershtein et al 2006; Collins et al 2006; Ekeberg et al 2013; Levy et al 2017; Harrigan et al 2018; Otten et al 2018; Rojas Echenique et al 2019; Shimagaki and Weigt 2019; de la Paz et al 2020; Rizzato et al 2020; Yang et al 2020; Bisardi et al 2022) and for the CoV-2 S protein in particular (Zeng et al 2020; Castiglione et al 2021; Dong et al 2021; Garvin et al 2021; Nielsen et al 2022; Ramarao-Milne et al 2022; Rochman et al 2022; Rodriguez-Rivas et al 2022). By showing dynamic differences between the interactions of CAPs, which have likely played a major role in allowing the virus to infect human hosts, the binding site, and the characteristic mutations of dominant Delta and Omicron strains, we see a “fine-tuning” of protein behavior.…”

Characteristics of replication and pathogenicity of SARS-CoV-2 Alpha and Delta isolates

“…With the persistent mutations of the Spike protein responsible for cell entry and immune escape under the evolutionary pressure from host ( Shu et al, 2021 ; Castiglione et al, 2021 ), it is important to monitor SARS-CoV-2 variants globally ( Tao et al, 2021 ). In the present study, the Alpha and Delta variants that were isolated from nasopharyngeal samples in Laos were characterized by replication kinetics in multiple cells and pathogenicity in both hACE2 transgenic mice and hamsters.…”

Human Ageing Genomic Resources: updates on key databases in ageing research

“…Of note in recent years, AnAge was used in a study to identify species with remarkable longevity with evolutionary implications for lifespan (39). AnAge has also facilitated data gathering on species’ maximum lifespan and relative age comparisons (40,41), body size values in a study exploring evolutionary pathways to SARS-CoV-2 resistance (42), and age of female sexual maturity in a major research endeavour on somatic mutation rates across mammals (43). HAGR’s data contributed to accurate predictions of basal metabolic rate and organ weights (44).…”