Differential spleen immune signatures and germinal center responses during acute infection with two clinical prevalent Orientia strains 2260067

Abstract

Abstract Introduction Scrub typhus is an emerging and neglected tropical disease caused by Orientia tsutsugamushi (Ot). Immunity in scrub typhus patients is known to be short-lived; however, its underlying mechanisms remain unclear. No reports have examined humoral immune signatures to clinically prevalent Ot strains. Methods In this study, we used Ot Karp and Gilliam strains and focused on splenic B cell and germinal center (GC) responses during acute infection in C57BL/6 mice for IF, RNAseq, and FACS analyses during acute infection. Results With the same infectious dose, Karp resulted in high tissue bacterium burdens and 50% mortality rates, Gilliam infection was self-healing with limited bacterium growth. Yet, Gilliam induced strong splenic B cell responses, as judged by total numbers of B cells, follicular B cells, and marginal zone B cells. Given that Karp- but not Gilliam-infected spleens displayed GC disorganization/loss and MZ abrogation, we compared splenic RNAseq profiles. On day 4 post-infection, Karp induced significant elevation of inflammation biomarkers (Ccl2, Il33, Ifng) and inflammatory pathways (Il1, Il6, Tnf, Ifng), the characteristics of severe scrub typhus. IPA analysis revealed Karp-induced neutrophil activation/degranulation and defense response pathways, which were in sharp contrast to Gilliam-induced upregulation of phagocytosis signaling pathways. Flow cytometry confirmed significantly higher influx of activated phagocyte subsets (neutrophils, M1 macrophages, and inflammatory monocytes) during Karp infection than Gilliam infection, indicating excessive inflammatory infiltration in severe infection. Conclusion Collectively, this study provides the first lines of evidence for Ot strain-related, cellular and humoral immune signatures, which help understand differential host immune responses during acute scrub typhus. Funding Source N/A Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)