Language

English

Publication Date

7-8-2025

Journal

JCI Insight

DOI

10.1172/jci.insight.191314

PMID

40402577

PMCID

PMC12306582

PubMedCentral® Posted Date

5-22-2025

PubMedCentral® Full Text Version

Post-print

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

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

Published Open-Access

yes

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