High-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 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.

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Publication Details

Journal
JCI Insight
Published
2025-05-22
DOI
https://doi.org/10.1172/jci.insight.191314
Citations
1
Primary Topic
COVID-19 Clinical Research Studies
Type
article
Field-Weighted Citation Impact
1.40

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article

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

Grace A. McComsey, Joann Diray‐Arce, Oscar A. Aguilar, Tasha Tsao et al.
1 citations
JCI Insight
COVID-19 Clinical Research Studies
1.40
article

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

Grace A. McComsey, Joann Diray‐Arce, Oscar A. Aguilar, Tasha Tsao, Lewis L. Lanier, Charles Langelier, Harry Pickering, David A. Hafler, Lauren I. R. Ehrlich, Daniel R. Calabrese, David J. Erle, Ruth R. Montgomery, William B. Messer, Viviana Simon, Esther Melamed, Jason D. Goldman, Albert C. Shaw, Bjoern Peters, Kari Christine Nadeau, Jordan P. Metcalf, Dylan Duchen, Bali Pulendran, Rafick‐Pierre Sékaly, Charles B. Cairns, Nadine Rouphael, Mark Davis, Christian Bime, Farrah Kheradmand, Catherine L. Hough, Shion A. Lim, Seunghee Kim‐Schulze, James A. Wells, Elaine F. Reed, Mark A. Atkinson, Joanna Schaenman, Carolyn S. Calfee, Monica Kraft, Steven H. Kleinstein, Ernie Chen, Ofer Levy, Holden T. Maecker, Florian Krammer, Yapeng Su, Patrice M. Becker, David B. Corry, Ana Fernández-Sesma, Nelson Iván Agudelo Higuita, Elias K. Haddad, Anita Qualls, Al Ozonoff, Irene Lui, Scott C. Brakenridge, Alison D. Augustine, Lindsey Robert Baden, James R. Heath
article en
1 citations

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.

JCI InsightVol. 10(13)
Brigham and Women's Hospital (US), Boston Children's Hospital (US), Michael E. DeBakey VA Medical Center (US), La Jolla Institute for Immunology (US), Harvard University (US), University of Arizona (US), Emory University (US), University of California, Los Angeles (US), Oregon Health & Science University (US), Palo Alto University (US), University of California, San Francisco (US), University of Washington (US), University Hospitals of Cleveland (US), Institute for Systems Biology (US), Yale University (US), University of Florida (US), Swedish Medical Center (US), Swedish Medical Center (US), Parker Institute for Cancer Immunotherapy (US), Chan Zuckerberg Initiative (United States) (US), National Institute of Allergy and Infectious Diseases (US), Boston Children's Museum (US), Precision Research (United States) (US), Atlanta VA Medical Center (US), Action Network (US), OU Health, University of Oklahoma Health Sciences Center (US), Seattle University (US), Case Western Reserve University (US), Drexel University (US), The University of Texas at Austin (US), Stanford University (US), Icahn School of Medicine at Mount Sinai (US)
Biomedical Advanced Research and Development Authority, National Institute of Allergy and Infectious Diseases, NIH Clinical Center
Zero hunger
Openalex Percentile: Top 20%
COVID-19 Clinical Research Studies
1.40
DOIOpen Access PDFOpenAlex
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