Genetic signature detected in T cell receptors from patients with severe COVID-19

Area of Science:

• Immunogenetics
• Virology
• Genomics

Background:

• Host genetic factors influence COVID-19 severity, with immune response pathways frequently implicated.
• Previous studies identified genome-wide associations with loss-of-function variants in immune pathways.
• Despite evidence for T cell involvement in COVID-19, definitive genetic markers for T cell responses were lacking.

Purpose of the Study:

• To identify host genetic factors associated with severe COVID-19.
• To investigate the role of T cell receptor beta (TRB) genes in COVID-19 pathogenesis.
• To explore potential genetic markers for T cell dysfunction in severe COVID-19.

Main Methods:

• Whole exome sequencing of 205 individuals (severe COVID-19 patients and controls).
• Analysis of high-impact alleles within the T cell receptor beta (TRB) locus.
• Assessment of variant enrichment and potential loss-of-function through compound heterozygosis.

Main Results:

• Identified 25 significantly enriched variants within the T cell receptor beta (TRB) locus.
• Observed potential TRB loss-of-function suggested by compound heterozygosis in specific TRBV genes (TRBV6-5, TRBV7-3, TRBV7-6, TRBV7-7, TRBV10-1).
• These genetic findings implicate TRB dysfunction in severe COVID-19.

Conclusions:

• Loss-of-function variants in TRB genes are associated with severe COVID-19.
• Suboptimal or dysfunctional T cell responses, driven by TRB genetic defects, may contribute significantly to severe COVID-19.
• These findings provide genetic evidence supporting T cell involvement and offer targets for drug discovery.