biostudies-literatureQualls AENational Institute of Allergy and Infectious DiseasesBLRD VABiomedical Advanced Research and Development AuthorityNIDDK NIH HHSNIDA NIH HHSNIAID NIH HHSNIH Clinical CenterNIH HHSNIGMS NIH HHSNational Science Foundatione191314https://www.ebi.ac.uk/biostudies/studies/S-EPMC12306582biostudies-literatureUnknown10(13)CD16A is an activating Fc receptor on NK cells that mediates antibody-dependent cellular cytotoxicity (ADCC), a key mechanism in antiviral immunity. However, the role of NK cell-mediated ADCC in SARS-CoV-2 infection remains unclear, particularly whether it limits viral spread and disease severity or contributes to the immunopathogenesis of COVID-19. We hypothesized that the high-affinity CD16AV176 polymorphism influences these outcomes. Using an in vitro reporter system, we demonstrated that CD16AV176 is a more potent and sensitive activator than the common CD16AF176 allele. To assess its clinical relevance, we analyzed 1,027 patients hospitalized with COVID-19 from the Immunophenotyping Assessment in a COVID-19 cohort (IMPACC), a comprehensive longitudinal dataset with extensive transcripJCI insightHigh-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19.PMC12306582R01AI145835-01A1S1R01 AI104870N01 AI025482U19 AI0626294U19AI090023-11U54 AI142766U19 AI1186105U19AI062629-175U19AI118608-045T33U19AI089992-09R01 AI122220U19 AI128910U19 AI1289135R01AI104870-074U19AI118610-06S10 OD0269405U19AI125357-05R01 AI135803P30 DK063720R56 AI1465813U19AI077439-13HHSO10201600031C3U19AI128913-03N01 AI0254965U54AI142766-03AI1465815U19AI128913-03T32 DA018926U19 AI0900235U19AI057229-17DMS2310836R01AI1222205U19AI128910-04U19 AI0774395R01AI135803-03I01 BX005023R01 AI145835U19 AI118608U19 AI057229U19 AI125357U19AI128913-04S1U19 AI0899923U19AI1289130R01 AI146581T32 GM141323Duchen DEhrlich LIPeters BHiguita NIALangelier CRSimon VKheradmand FAugustine ADRouphael NMaecker HTPickering HMcComsey GASekaly RPCorry DBDavis MMReed EFSu YMetcalf JPHaddad EKDiray-Arce JOzonoff AMelamed ECairns CBKim-Schulze SBaden LRBrakenridge SCPulendran BChen EHough CLNadeau KCMontgomery RRKraft MBime CLevy OIMPACC NetworkCalabrese DRWells JAGoldman JDLanier LLHafler DASchaenmann JCalfee CSHeath JRKrammer FAguilar OALim SAErle DJKleinstein SHTsao TShaw ACMesser WBLui IQualls AEAtkinson MAFernandez-Sesma ABecker PMfalseHigh-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19.CD16A is an activating Fc receptor on NK cells that mediates antibody-dependent cellular cytotoxicity (ADCC), a key mechanism in antiviral immunity. However, the role of NK cell-mediated ADCC in SARS-CoV-2 infection remains unclear, particularly whether it limits viral spread and disease severity or contributes to the immunopathogenesis of COVID-19. We hypothesized that the high-affinity CD16AV176 polymorphism influences these outcomes. Using an in vitro reporter system, we demonstrated that CD16AV176 is a more potent and sensitive activator than the common CD16AF176 allele. To assess its clinical relevance, we analyzed 1,027 patients hospitalized with COVID-19 from the Immunophenotyping Assessment in a COVID-19 cohort (IMPACC), a comprehensive longitudinal dataset with extensive transcrip2025-01-01T00:00:00Z2025 Jul2026-03-27T16:51:53.661Z2025-08-27T03:11:07.142ZS-EPMC123065824040257710.1172/jci.insight.191314