Enhanced EBNA2-dependent activity in EBV-transformed B cells from patients with multiple sclerosis

Area of Science:

• Immunology
• Neuroscience
• Virology

Background:

• Multiple sclerosis (MS) is an immune-mediated disease influenced by genetic and environmental factors.
• Epstein-Barr virus (EBV) infection is a significant environmental risk factor for MS.
• The precise molecular mechanisms linking EBV to MS pathogenesis remain incompletely understood.

Purpose of the Study:

• To investigate the impact of EBV infection on gene expression, chromatin accessibility, and transcription factor binding in B cells from MS patients.
• To elucidate the role of the EBV-encoded protein EBNA2 in MS pathogenesis.
• To explore the interaction between EBV and host genetic risk factors in MS.

Main Methods:

• RNA-sequencing (RNA-seq) and ATAC-sequencing (ATAC-seq) were performed on primary and EBV-transformed B cells from MS patients and healthy controls.
• Chromatin immunoprecipitation sequencing (ChIP-seq) was used to analyze EBNA2 binding sites and interactions with human partners.
• Gene expression, chromatin accessibility, and transcription factor binding were compared between MS-derived and control cells.

Main Results:

• EBV-transformed B cells from MS patients showed significant MS-dependent changes in gene expression and chromatin accessibility compared to controls.
• These alterations were largely attributed to the expression levels of EBNA2, an EBV transcriptional regulator.
• EBNA2 binding was enriched at MS genetic risk loci, with increased allelic binding and enrichment in MS-derived cells, involving interactions with RBPJ, EBF1, and PU.1.

Conclusions:

• Enhanced EBNA2 activity in MS significantly alters human gene expression, chromatin accessibility, and transcription factor binding in an MS-dependent manner.
• EBV, particularly EBNA2, interacts with host genetic susceptibility to contribute to the molecular mechanisms underlying MS.
• This study provides critical insights into the interplay between viral infection and host genetics in the development of multiple sclerosis.