Host Genetic Architecture between Epstein-Barr Virus Activity and Multiple Sclerosis Reveals Shared Pathways

Area of Science:

• Genetics
• Immunology
• Virology

Background:

• Epstein-Barr virus (EBV) is a suspected trigger for multiple sclerosis (MS), but the underlying genetic and cellular mechanisms remain unclear.
• Understanding host genetic factors influencing EBV activity is crucial for elucidating its role in MS pathogenesis.

Purpose of the Study:

• To identify host genetic loci associated with EBV DNA positivity.
• To investigate the cellular mechanisms by which EBV infection may trigger MS.
• To establish a genetic and cellular framework linking EBV to MS initiation.

Main Methods:

• Developed a pipeline to quantify EBV DNA from whole-genome sequencing data.
• Performed a cross-ancestry genome-wide association study (GWAS) in over 600,000 individuals.
• Utilized quantitative PCR (qPCR), polygenic risk scores (PRS), Mendelian randomization, and single-cell RNA sequencing (scRNA-seq).

Main Results:

• Identified 39 independent genetic loci associated with EBV DNA positivity, predominantly in the HLA region.
• Found a significant overlap between genetic variants linked to EBV and MS risk.
• Detected EBV-infected B cells, particularly memory and atypical B cells, which upregulate immune-activating molecules and MS risk genes.
• Mendelian randomization supported a causal role for EBV activity in MS risk.

Conclusions:

• Established a genetic and cellular framework connecting EBV infection to MS initiation.
• EBV-infected B cells act as a critical hub modulating T cell responses and activating MS susceptibility pathways.
• Genetic predisposition influences EBV activity, potentially leading to autoimmune responses like MS.