Journal article
High affinity CD16 polymorphism associated with reduced risk of severe COVID-19
JCI insight, v 10(13), e191314
22 May 2025
PMID: 40402577
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
CD16 is an activating Fc receptor on natural killer 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 a novel 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 hospitalized COVID-19 patients 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 CD16 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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Details
- Title
- High affinity CD16 polymorphism associated with reduced risk of severe COVID-19
- Creators
- Anita E Qualls - University of California, San FranciscoTasha Tsao - University of California, San FranciscoIrene Lui - University of California, San FranciscoShion A Lim - University of California, San FranciscoYapeng Su - Institute for Systems BiologyErnie Chen - Yale UniversityDylan Duchen - Yale UniversityHolden T Maecker - Stanford UniversitySeunghee Kim-Schulze - Icahn School of Medicine at Mount SinaiRuth R Montgomery - Yale UniversityFlorian Krammer - Icahn School of Medicine at Mount SinaiCharles R Langelier - Department of Medicine, UCSF, San Francisco, United States of AmericaOfer Levy - Boston Children's HospitalLindsey R Baden - Brigham and Women's HospitalEsther Melamed - The University of Texas at AustinLauren Ir Ehrlich - The University of Texas at AustinGrace A McComsey - University Hospitals of ClevelandRafick P Sekaly - Case Western Reserve UniversityCharles B Cairns - Drexel UniversityElias K Haddad - Drexel UniversityAlbert C Shaw - Yale UniversityDavid A Hafler - Yale UniversityDavid B Corry - Baylor College of MedicineFarrah Kheradmand - Michael E. DeBakey VA Medical CenterMark A Atkinson - University of FloridaScott C Brakenridge - University of FloridaNelson I Agudelo Higuita - OU HealthJordan P Metcalf - University of Oklahoma Health Sciences CenterCatherine L Hough - Oregon Health & Science UniversityWilliam B Messer - Oregon Health & Science UniversityBali Pulendran - Stanford UniversityKari C Nadeau - Stanford UniversityMark M Davis - Stanford UniversityAna Fernandez-Sesma - Icahn School of Medicine at Mount SinaiViviana Simon - Icahn School of Medicine at Mount SinaiMonica Kraft - University of ArizonaChristian Bime - University of ArizonaCarolyn S Calfee - Department of Medicine, UCSF, San Francisco, United States of AmericaDavid J Erle - Department of Medicine, UCSF, San Francisco, United States of AmericaJoanna Schaenmann - David Geffen School of Medicine at UCLAAl Ozonoff - Boston Children's HospitalBjoern Peters - La Jolla Institute for ImmunologySteven H Kleinstein - Yale UniversityAlison D Augustine - National Institute of Allergy and Infectious DiseasesJoann Diray-Arce - Boston Children's HospitalPatrice M Becker - National Institute of Allergy and Infectious DiseasesNadine Rouphael - Emory and Henry CollegeImpacc Network - Boston UniversityJason D Goldman - University of WashingtonDaniel R Calabrese - Department of Medicine, UCSF, San Francisco, United States of AmericaJames R Heath - Institute for Systems BiologyJames A Wells - University of California, San FranciscoElaine F Reed - University of California, Los AngelesLewis L Lanier - University of California, San FranciscoHarry Pickering - University of California, Los AngelesOscar A Aguilar - University of California, San Francisco
- Publication Details
- JCI insight, v 10(13), e191314
- Publisher
- American Society for Clinical Investigation
- Number of pages
- 20
- Grant note
- National Institute of Allergy and Infectious Diseases, NIH: NO1-AI-25496, NO1-AI-25482 DRC Center Grant: NIH P30 DK063720 NIH: P30 DK063720, S10 1S10OD026940-01, AI146581, 5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, R01AI122220 NIH MSTP training grant: 5T32GM141323 Cancer Research Institute (CRI)Parker Institute for Cancer Immunotherapy (PICI)National Science Foundation: DMS2310836 BARDA: HHSO10201600031C
We thank Chris Chang, Peter Hunt, and Lanier lab members for critical discussions of this work. This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, NIH, under contract nos. NO1-AI-25496 and NO1-AI-25482. See Supplemental Acknowledgments for details on the IMPACC Network. We thank Vitalant for donating convalescent plasma for optimizing our assay. We thank the UCSF Parnassus Flow Core (RRID:SCR_018206) (which is supported by DRC Center Grant NIH P30 DK063720, in part by grant NIH P30 DK063720, and by the instrumentation grant NIH S10 1S10OD026940-01) for help and advice. AEQ is supported by the NIH MSTP training grant 5T32GM141323. OAA held a Postdoctoral Enrichment Program Award from the Burroughs Wellcome Fund (BWF) and a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute (CRI) . OAA and LLL are supported by the Parker Institute for Cancer Immunotherapy (PICI) and NIH grant AI146581. The study was also supported by NIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, R01AI122220) ; and National Science Foundation (DMS2310836) and BARDA (HHSO10201600031C) .
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine; Infectious Diseases (and HIV Medicine); Emergency Medicine
- Web of Science ID
- WOS:001528973300001
- Scopus ID
- 2-s2.0-105010869215
- Other Identifier
- 991022054334004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Medicine, Research & Experimental