TY - JOUR
T1 - Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2
AU - Suryamohan, Kushal
AU - Diwanji, Devan
AU - Stawiski, Eric W.
AU - Gupta, Ravi
AU - Miersch, Shane
AU - Liu, Jiang
AU - Chen, Chao
AU - Jiang, Ying Ping
AU - Fellouse, Frederic A.
AU - Sathirapongsasuti, J. Fah
AU - Albers, Patrick K.
AU - Deepak, Tanneeru
AU - Saberianfar, Reza
AU - Ratan, Aakrosh
AU - Washburn, Gavin
AU - Mis, Monika
AU - Santhosh, Devi
AU - Somasekar, Sneha
AU - Hiranjith, G. H.
AU - Vargas, Derek
AU - Mohan, Sangeetha
AU - Phalke, Sameer
AU - Kuriakose, Boney
AU - Antony, Aju
AU - Ustav, Mart
AU - Schuster, Stephan C.
AU - Sidhu, Sachdev
AU - Junutula, Jagath R.
AU - Jura, Natalia
AU - Seshagiri, Somasekar
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - COVID-19 is a respiratory illness caused by a novel coronavirus called SARS-CoV-2. The viral spike (S) protein engages the human angiotensin-converting enzyme 2 (ACE2) receptor to invade host cells with ~10–15-fold higher affinity compared to SARS-CoV S-protein, making it highly infectious. Here, we assessed if ACE2 polymorphisms can alter host susceptibility to SARS-CoV-2 by affecting this interaction. We analyzed over 290,000 samples representing >400 population groups from public genomic datasets and identified multiple ACE2 protein-altering variants. Using reported structural data, we identified natural ACE2 variants that could potentially affect virus–host interaction and thereby alter host susceptibility. These include variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R that were predicted to increase susceptibility, while variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y were predicted to be protective variants that show decreased binding to S-protein. Using biochemical assays, we confirmed that K31R and E37K had decreased affinity, and K26R and T92I variants showed increased affinity for S-protein when compared to wildtype ACE2. Consistent with this, soluble ACE2 K26R and T92I were more effective in blocking entry of S-protein pseudotyped virus suggesting that ACE2 variants can modulate susceptibility to SARS-CoV-2.
AB - COVID-19 is a respiratory illness caused by a novel coronavirus called SARS-CoV-2. The viral spike (S) protein engages the human angiotensin-converting enzyme 2 (ACE2) receptor to invade host cells with ~10–15-fold higher affinity compared to SARS-CoV S-protein, making it highly infectious. Here, we assessed if ACE2 polymorphisms can alter host susceptibility to SARS-CoV-2 by affecting this interaction. We analyzed over 290,000 samples representing >400 population groups from public genomic datasets and identified multiple ACE2 protein-altering variants. Using reported structural data, we identified natural ACE2 variants that could potentially affect virus–host interaction and thereby alter host susceptibility. These include variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R that were predicted to increase susceptibility, while variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y were predicted to be protective variants that show decreased binding to S-protein. Using biochemical assays, we confirmed that K31R and E37K had decreased affinity, and K26R and T92I variants showed increased affinity for S-protein when compared to wildtype ACE2. Consistent with this, soluble ACE2 K26R and T92I were more effective in blocking entry of S-protein pseudotyped virus suggesting that ACE2 variants can modulate susceptibility to SARS-CoV-2.
UR - http://www.scopus.com/inward/record.url?scp=85104272913&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104272913&partnerID=8YFLogxK
U2 - 10.1038/s42003-021-02030-3
DO - 10.1038/s42003-021-02030-3
M3 - Article
C2 - 33846513
AN - SCOPUS:85104272913
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 475
ER -
