High-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19

JCI Insight. 2025 May 22;10(13):e191314. doi: 10.1172/jci.insight.191314. eCollection 2025 Jul 8.

Abstract

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 transcriptomic, proteomic, and clinical data. The high-affinity CD16AV176 allele was associated with a significantly reduced risk of ICU admission, mechanical ventilation, and severe disease trajectories. Lower anti-SARS-CoV-2 IgG titers were correlated to CD16AV176; however, there was no difference in viral load across CD16A genotypes. Proteomic analysis revealed that participants homozygous for CD16AV176 had lower levels of inflammatory mediators. These findings suggest that CD16AV176 enhances early NK cell-mediated immune responses, limiting severe respiratory complications in COVID-19. This study identifies a protective genetic factor against severe COVID-19, informing future host-directed therapeutic strategies.

Keywords: COVID-19; Cellular immune response; Immunology; Innate immunity; NK cells.

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Antibody-Dependent Cell Cytotoxicity / genetics
  • Antibody-Dependent Cell Cytotoxicity / immunology
  • COVID-19* / genetics
  • COVID-19* / immunology
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Killer Cells, Natural / immunology
  • Male
  • Middle Aged
  • Polymorphism, Genetic
  • Receptors, IgG* / genetics
  • Receptors, IgG* / immunology
  • SARS-CoV-2 / immunology
  • Severity of Illness Index
  • Viral Load

Substances

  • Receptors, IgG
  • FCGR3A protein, human