Unveiling the Immune Landscape: Single‐Cell Sequencing of Infectious Mononucleosis Patients

This study employed single-cell sequencing to analyze immune dynamics in pediatric infectious mononucleosis (IM), focusing on EBV-host interactions. EBV primarily infected B-cell subsets, showing distinct tropism from EBV-associated hemophagocytic syndrome, indicating stage-specific infection patterns. Coexpression of lytic (BALF3/5) and latent (EBNA-3A, LMP-2A) genes suggested dynamic infection states. Notably, RPMS1 expression was consistently detected in IM patients, where this oncogenic regulator influences viral latency maintenance and cellular transformation through Notch signaling. NK cell subsets exhibited differential responses: CD16 + CD56dim NK cells demonstrated enhanced EBV cytotoxicity, while CD16 - CD56bright NK cells showed immunoregulatory potential. Clonal expansion of IGHV4-34/59 in B cells (involved in EBV gp350 binding and autoimmunity) suggested dual roles in viral neutralization and pathogenesis. Frequent IGHJ4/IGLJ3 BCR rearrangements informed vaccine design. Elevated COTL1 in T cells correlated with pro-inflammatory cytokine release, indicating therapeutic potential. Dysregulated IRF4/PRDM1 in plasma cells reflected interindividual EBV control variability. These findings delineate IM immunopathology, linking EBV persistence to clonal expansion and immune evasion, while providing a framework for targeted therapies (NK cell engineering, IGHV4-directed antibodies, COTL1 modulation) to advance EBV-associated disease treatment.