Dysregulated B Cell Responses in Severe Fever With Thrombocytopenia Syndrome Revealed by Single‐Cell RNA Sequencing

Severe fever with thrombocytopenia syndrome virus (SFTSV) infection is associated with poor clinical outcomes and defective humoral immunity yet the immunometabolic mechanisms underlying B cell dysfunction remain incompletely defined. Through integrated single-cell RNA sequencing and B cell receptor (BCR) repertoire profiling of peripheral B cells from SFTS patients, we dissected the molecular signatures between survivors and fatal cases. Functional validation and metabolic flux analysis were further performed. Seven transcriptionally distinct B cell subsets were identified. Fatal cases exhibited a marked expansion of CXCR3+Ki-67+CXCR5- extrafollicular plasmablasts, coupled with depletion of naïve and memory B cells. These plasmablasts exhibited hyperactivation of interferon-response genes (IFI27, ISG15), upregulation of inflammatory mediators (S100A8/A9), and contraction of BCR diversity, with skewed usage of λ-light chains. Pseudotime trajectory analysis and metabolic scoring revealed progressive upregulation of oxidative phosphorylation, glycolysis and endoplasmic reticulum stress during terminal differentiation. In fatal cases, B cells exhibited suppressed antigen presentation capacity and impaired immunoglobulin gene expression, alongside heightened oxidative stress and elevated CD39 levels. Furthermore, analysis of SFTSV-infected versus uninfected B cells revealed that infected plasmablasts displayed enhanced inflammatory and migratory features, including upregulated CXCR3 and CCR10 expression, suggesting direct viral modulation of B cell function and trafficking. Our study reveals that dysfunctional, metabolically reprogrammed plasmablasts underlie humoral immune failure in fatal SFTS. These findings provide mechanistic insight into B cell-mediated immunopathogenesis and highlight potential targets for prognostic evaluation and immunomodulatory intervention.