IFNAR2 p.F8S Variant Associates with Severe COVID-19 and Adaptive Immune Cell Activation Modulation.

Area of Science:

• Genetics
• Immunology
• Virology

Background:

• Genetic factors influence the diverse clinical spectrum of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.
• Understanding these genetic determinants is crucial for elucidating COVID-19 pathogenesis.

Purpose of the Study:

• To identify genetic variants impacting protein sequence associated with severe COVID-19.
• To investigate the functional consequences of identified variants on immune responses.

Main Methods:

• Case-control association studies using the Milan FOGS and COVID-19 Host Genetics Initiative cohorts.
• Analysis of circulating IL-6 levels and peripheral blood mononuclear cell (PBMC) transcriptomics.
• Functional validation using flow cytometry and single-cell RNA sequencing (scRNAseq) data.

Main Results:

• The low-frequency p.F8S variant in the interferon alpha receptor 2 (IFNAR2) gene was independently associated with severe COVID-19.
• p.F8S carriers exhibited higher IL-6 levels and upregulated immune/pathogen response pathways in PBMCs.
• Functional studies showed altered IFNAR2 membrane expression and enhanced immune pathway activation in dendritic cells of carriers.

Conclusions:

• The IFNAR2 p.F8S variant is a potential genetic determinant of severe COVID-19.
• This variant may exacerbate disease by modulating immune cell function, particularly enhancing adaptive immune responses and inflammation in dendritic cells.