Journal
PLOS COMPUTATIONAL BIOLOGY
Volume 18, Issue 3, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pcbi.1009922
Keywords
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Funding
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/J019364/1, BB/R014752/1]
- Wellcome Trust Biomedical Resources Grant [101651/Z/13/Z]
- Wellcome Trust Senior Fellowship in Basic Biomedical Sciences [207537/Z/17/Z828]
- Wellcome Trust [101651/Z/13/Z] Funding Source: Wellcome Trust
- BBSRC [BB/R014752/1, BB/J019364/1] Funding Source: UKRI
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This study investigated the impact of ACE2 gene variants on SARS-CoV-2 infection. The research found that certain ACE2 variants can reduce the binding capability between the virus and host cells, thus protecting cells from infection, while other variants enhance the binding capability, potentially leading to wider viral spreading across tissues and cell types.
SARS-CoV-2 Spike (Spike) binds to human angiotensin-converting enzyme 2 (ACE2) and the strength of this interaction could influence parameters relating to virulence. To explore whether population variants in ACE2 influence Spike binding and hence infection, we selected 10 ACE2 variants based on affinity predictions and prevalence in gnomAD and measured their affinities and kinetics for Spike receptor binding domain through surface plasmon resonance (SPR) at 37 degrees C. We discovered variants that reduce and enhance binding, including three ACE2 variants that strongly inhibited (p.Glu37Lys, Delta Delta G = -1.33 +/- 0.15 kcal mol(-1) and p.Gly352Val, predicted Delta Delta G = -1.17 kcal mol(-1)) or abolished (p.Asp355Asn) binding. We also identified two variants with distinct population distributions that enhanced affinity for Spike. ACE2 p.Ser19Pro (Delta Delta G = 0.59 +/- 0.08 kcal mol(-1)) is predominant in the gnomAD African cohort (AF = 0.003) whilst p.Lys26Arg (Delta Delta G = 0.26 +/- 0.09 kcal mol(-1)) is predominant in the Ashkenazi Jewish (AF = 0.01) and European non-Finnish (AF = 0.006) cohorts. We compared ACE2 variant affinities to published SARS-CoV-2 pseudotype infectivity data and confirmed that ACE2 variants with reduced affinity for Spike can protect cells from infection. The effect of variants with enhanced Spike affinity remains unclear, but we propose a mechanism whereby these alleles could cause greater viral spreading across tissues and cell types, as is consistent with emerging understanding regarding the interplay between receptor affinity and cell-surface abundance. Finally, we compared mCSM-PPI2 Delta Delta G predictions against our SPR data to assess the utility of predictions in this system. We found that predictions of decreased binding were well-correlated with experiment and could be improved by calibration, but disappointingly, predictions of highly enhanced binding were unreliable. Recalibrated predictions for all possible ACE2 missense variants at the Spike interface were calculated and used to estimate the overall burden of ACE2 variants on Covid-19.
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