VirTrack: A Framework for Inferring Viral Influence on Disease-Associated Transcriptomes -- Clinical Type-Specific Epstein-Barr Virus Pathogenesis in Multiple Sclerosis

BackgroundEpstein-Barr virus (EBV) is strongly implicated in Multiple Sclerosis (MS), but how its influence varies across MS clinical types remains unclear. MethodsWe developed VirTrack, a computational framework that integrates experimentally validated EBV-host protein-protein interactions (PPIs) with clinical type-specific peripheral blood transcriptomes from Clinically Isolated Syndrome (CIS), Relapsing Remitting MS (RRMS), Secondary Progressive MS (SPMS), and Primary Progressive MS (PPMS) (GSE136411). VirTrack (i) anchors viral interactions in differentially expressed genes (DEGs), (ii) ranks EBV targeting of DEGs and host hubs, and (iii) applies machine learning- based clustering to identify clinical type-specific functional pathways influenced by EBV. ResultsEBV engagement was clinical type-dependent. In early MS (CIS and RRMS), EBV targeted approximately 13-18% of dysregulated genes, enriching for B-cell-related processes, Toll-like receptor signaling, and infection-like inflammatory pathways, while suppressing antiviral and NF-{kappa}B responses. Progressive clinical types exhibited fewer viral connections but distinct mechanistic shifts: SPMS was characterized by suppression of vascular and cardiac repair-associated pathways, whereas PPMS was dominated by upregulation of vacuolar and lysosomal remodeling processes. Hub analyses revealed a stable core of influential EBV proteins, EBNA-LP (consistently top-ranked), BZLF1, BVLF1, LMP2, and BDLF4, while BNLF2A showed broad but less hub-focused targeting and LMP1 ranked low across types. ConclusionEBV shapes MS through dynamic, clinical type-specific perturbations, driving strong immunomodulation in early disease and selective cellular remodeling during progressive types. VirTrack identifies key viral proteins and host pathways for stage-tailored therapeutic targeting, supporting early EBV-directed interventions and revealing potential links to vascular comorbidity in progressive MS types. More broadly, VirTrack offers a generalizable, systems-level framework for elucidating viral contributions across complex human diseases.