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High-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19
Anita E Qualls1, Tasha Tsao1, Irene Lui2
1Department of Microbiology and Immunology, UCSF, San Francisco, California, USA.
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.
Insights
The high-affinity CD16AV176 gene variant enhances natural killer cell responses against SARS-CoV-2, reducing severe COVID-19. This genetic factor lowers the risk of intensive care unit admission and mechanical ventilation in patients.
Area of Science:
- Immunology
- Genetics
- Virology
Background:
- Natural killer (NK) cells and CD16A receptors are crucial for antiviral immunity via antibody-dependent cellular cytotoxicity (ADCC).
- The specific role of NK cell-mediated ADCC in SARS-CoV-2 infection and its impact on COVID-19 severity remain incompletely understood.
- The CD16A V176 polymorphism, a high-affinity variant, was hypothesized to influence COVID-19 outcomes.
Purpose of the Study:
- To investigate the functional differences between CD16AV176 and CD16AF176 alleles in vitro.
- To determine the clinical relevance of the CD16AV176 polymorphism in a large cohort of hospitalized COVID-19 patients.
- To explore the association between CD16A genotypes and disease severity, viral load, and inflammatory profiles.
Main Methods:
- An in vitro reporter system was used to compare the activation potency and sensitivity of CD16AV176 and CD16AF176 alleles.
- Clinical data, including ICU admission and mechanical ventilation, were analyzed from 1,027 hospitalized COVID-19 patients in the IMPACC cohort.
- Transcriptomic, proteomic, and viral load data were assessed in relation to CD16A genotypes.
Main Results:
- The CD16AV176 allele demonstrated significantly higher potency and sensitivity as an activator compared to CD16AF176.
- Patients with the CD16AV176 allele showed a reduced risk of ICU admission, mechanical ventilation, and severe COVID-19.
- While lower anti-SARS-CoV-2 IgG titers correlated with CD16AV176, no differences in viral load were observed; however, homozygous CD16AV176 individuals exhibited lower inflammatory mediator levels.
Conclusions:
- The high-affinity CD16AV176 polymorphism is associated with a protective effect against severe COVID-19.
- Enhanced NK cell-mediated responses due to CD16AV176 may limit severe respiratory complications.
- This genetic factor offers insights for developing host-directed therapeutic strategies for COVID-19.
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