Unique Humoral Immune Responses in Mice with Mild and Severe Outcomes of Scrub Typhus 2353

Description Scrub typhus is an understudied mite-borne disease, caused by intracellular bacteria Orientia tsutsugamushi (Ot). Humoral immunity in scrub typhus patients is short-lived, but the underlying mechanism remains unknown. There is also a knowledge gap regarding adaptive immune responses to clinically prevalent Ot strains, in humans or experimental animal models. This study used C57BL/6 mice with severe (Karp) and self-limiting Ot infection (Gilliam) with an objective of defining strain-associated differences in B cell and germinal center (GC) responses. Compared to the Karp counterparts, Gilliam-infected mice had lower splenic bacterial burdens, but showed 1) higher IgM, IgG, and IgG2c responses, 2) strong follicular and marginal zone B cell responses and expansion of regulatory T cell subsets, and 3) evidence of organized GCs that were maintained throughout infection. To verify whether GC loss during Karp infection was due to poorly regulated, excessive inflammatory responses, we compared spleen RNAseq profiles. Karp-infected mice had significant upregulation of pathways involved in inflammation (TNF, IFNg, IL-1) and recruitment of innate immune cells (neutrophils, eosinophils, macrophages, mononuclear cells) on days 4 and 8. In contrast, Gilliam-infected mice upregulated genes involved with B and T cell responses at day 12. Collectively, these Ot strain-related patterns help fill the knowledge gap of adaptive immune responses and explain transient immunity to scrub typhus. Funding Sources NIAID R01 AI132674 NIAID R21 AI156536 NIH T32-AI060549 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)