rs71327024 Associated with COVID-19 Hospitalization Reduces CXCR6 Promoter Activity in Human CD4+ T Cells via
Aksinya N Uvarova1,2, Ekaterina M Stasevich1, Alina S Ustiugova1
1Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
Insights
A common genetic variant near the CXCR6 gene increases severe COVID-19 hospitalization risk. This variant disrupts a transcription factor binding site, potentially lowering CXCR6 expression in T helper cells and worsening inflammatory diseases.
Area of Science:
- Immunology
- Genetics
- Virology
Background:
- Single-nucleotide polymorphism (SNP) rs71327024 in the 3p21.31 locus is linked to increased hospitalization risk from SARS-CoV-2 infection.
- The 3p21.31 locus includes genes for chemokine receptors, such as CXCR6, which is crucial for immune cell recruitment in inflammatory and respiratory conditions.
- Reduced CXCR6 expression in lung T cells correlates with severe COVID-19 outcomes.
Purpose of the Study:
- To investigate the functional role of SNP rs71327024 in regulating CXCR6 expression.
- To determine the molecular mechanism by which this SNP influences COVID-19 severity.
Main Methods:
- Analysis of rs71327024's location within an active enhancer region.
- Reporter assays to assess the impact of rs71327024 variants on CXCR6 promoter activity in CD4+ T lymphocytes.
- Electrophoretic mobility shift assays (EMSA) to evaluate c-Myb transcription factor binding.
- c-Myb knockdown experiments in Jurkat cells.
Main Results:
- rs71327024 is situated in an enhancer that modulates CXCR6 promoter activity.
- The common rs71327024(G) allele creates a functional c-Myb binding site, while the risk allele rs71327024(T) disrupts this binding and reduces enhancer activity.
- c-Myb knockdown confirmed the allele-specific effects of rs71327024 on CXCR6 expression.
Conclusions:
- Disruption of the c-Myb binding site by the rs71327024(T) allele may lead to decreased CXCR6 expression in T helper cells.
- This reduction in CXCR6 could contribute to the progression of severe COVID-19 and other inflammatory diseases.
Abstract:
Single-nucleotide polymorphism rs71327024 located in the human 3p21.31 locus has been associated with an elevated risk of hospitalization upon SARS-CoV-2 infection. The 3p21.31 locus contains several genes encoding chemokine receptors potentially relevant to severe COVID-19. In particular, CXCR6, which is prominently expressed in T lymphocytes, NK, and NKT cells, has been shown to be involved in the recruitment of immune cells to non-lymphoid organs in chronic inflammatory and respiratory diseases. In COVID-19, CXCR6 expression is reduced in lung resident memory T cells from patients with severe disease as compared to the control cohort with moderate symptoms. We demonstrate here that rs71327024 is located within an active enhancer that augments the activity of the CXCR6 promoter in human CD4+ T lymphocytes. The common rs71327024(G) variant makes a functional binding site for the c-Myb transcription factor, while the risk rs71327024(T) variant disrupts c-Myb binding and reduces the enhancer activity. Concordantly, c-Myb knockdown in PMA-treated Jurkat cells negates rs71327024's allele-specific effect on CXCR6 promoter activity. We conclude that a disrupted c-Myb binding site may decrease CXCR6 expression in T helper cells of individuals carrying the minor rs71327024(T) allele and thus may promote the progression of severe COVID-19 and other inflammatory pathologies.
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