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

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.