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• W4316011694 abstract "Abstract Scrub typhus is a poorly studied but life-threatening disease caused by the intracellular bacterium Orientia tsutsugamushi ( Ot ). Cellular and humoral immunity in Ot -infected patients is not long-lasting, waning as early as one-year post-infection; however, its underlying mechanisms remain unclear. To date, no studies have examined germinal center (GC) or B cell responses in Ot -infected humans or experimental animals. This study was aimed at evaluating humoral immune responses at acute stages of severe Ot infection and possible mechanisms underlying B cell dysfunction. Following inoculation with Ot Karp, a clinically dominant strain known to cause lethal infection in C57BL/6 mice, we measured antigen-specific antibody titers, revealing IgG2c as the dominant isotype induced by infection. Splenic GC responses were evaluated by immunohistology, co-staining for B cells (B220), T cells (CD3), and GCs (GL-7). Organized GCs were evident at day 4 post-infection (D4), but they were nearly absent at D8, accompanied by scattered T cells throughout splenic tissues. Flow cytometry revealed comparable numbers of GC B cells and T follicular helper (Tfh) cells at D4 and D8, indicating that GC collapse was not due to excessive death of these cell subtypes at D8. B cell RNAseq analysis revealed significant differences in expression of genes associated with B cell adhesion and co-stimulation at D8 versus D4. The significant downregulation of S1PR2 (a GC-specific adhesion gene) was most evident at D8, correlating with disrupted GC formation. Signaling pathway analysis uncovered downregulation of 71% of B cell activation genes at D8, suggesting attenuation of B cell activation during severe infection. This is the first study showing the disruption of B/T cell microenvironment and dysregulation of B cell responses during Ot infection, which may help understand the transient immunity associated with scrub typhus. Author Summary Scrub typhus is an understudied disease caused by the intracellular bacterium O. tsutsugamushi . A hallmark of scrub typhus is the unexplained, non-durable immunity after infection. While cellular immune responses are known to be important for controlling this infection, our understanding of B cell and GC responses remains limited. In this study, we examined B cell activation and GC responses using our recently established murine model of severe scrub typhus. We measured bacterial antigen-specific antibody titers and identified IgG2c, an IFN-γ-driven isotype, as the major IgG subtype. We also found that O. tsutsugamushi infection disrupted spleen morphology, exemplified by randomly dispersed T cells and lost GC structures. Transcriptomic analysis of purified splenic B cells demonstrated reduced expression of genes encoding critical adhesion and co-stimulation molecules, including GC-adhesion gene S1PR2 , at severe stages of infection. Several humoral immune response pathways relevant to B cell receptor signaling, B cell activation and differentiation were significantly downregulated during infection. This study is the first report describing humoral immunity in a scrub typhus mouse model and provides detailed evidence that B cell and GC responses are impaired during acute infection." @default.
• W4316011694 created "2023-01-14" @default.
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• W4316011694 date "2023-01-13" @default.
• W4316011694 modified "2023-10-18" @default.
• W4316011694 title "Alterations in Germinal Center Formation and B Cell Activation during Severe<i>Orientia tsutsugamushi</i>Infection in Mice" @default.
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• W4316011694 doi "https://doi.org/10.1101/2023.01.12.523709" @default.
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