High-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19
Anita E. Qualls, et al.
Anita E. Qualls, et al.
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Research Article COVID-19 Immunology

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

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.

Authors

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

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Figure 4

High-affinity CD16AV176 is associated with lower anti–SARS-CoV-2 antibody titers and globally reduced soluble mediators of inflammation.

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High-affinity CD16AV176 is associated with lower anti–SARS-CoV-2 antibod...
(A) Antibody levels against SARS-CoV-2 RBD were measured via ELISA as AUC and stratified by CD16A genotype (P = 5.6 × 10–4). (B) Antibody levels against SARS-CoV-2 spike were measured via ELISA and stratified by CD16A genotype (P = 0.001). (C) SARS-CoV-2 viral load reported as viral reads per million (rpM) was determined from nasal metagenomics and compared across CD16A genotypes (P = 0.148). Data from A–C are from cisit 1 (<48 hours from hospital admission). (D) Oligonucleotide-linked antibody detection (Olink) was performed on n = 948 participants to quantify cytokines, chemokines, and soluble receptors in serum. Displayed are the 12 that were significantly different across CD16A genotypes (P ≤ 0.05) after correcting for multiple testing. CC, homozygous high affinity. (E and F) Cytometry by time of flight (CyTOF) was performed on whole blood of n = 788 participants and immune cell counts were determined. NK cell counts (P = 0.136) in E and CD39loCD4+ Treg counts (P = 3.0 × 10–6) in F were recorded split by CD16A genotype. Analyses were modeled as clinical outcome-Y on CD16AV176 variant allele count-X by linear regression.