Scrub typhus is an emerging, insect-transmitted disease caused by Orientia tsutsugamushi, a Gram- and LPS-negative bacterium that replicates freely within professional phagocytes and endothelial cells. Scrub typhus is prevalent with high mortality rates, but information regarding its molecular pathogenesis, microbial virulence determinants, and key immune responses is limited. Improved animal models have recently been developed that respectively resemble the pathological features of self-limiting or severe scrub typhus in humans. Strong activation of Th1 and CD8, but not Th2 and regulatory T, immune responses, accompanied by altered angiopoietin/Tie2-related regulation, are hallmarks of lethal infection in murine models. This review, based primarily on recent advances from clinical and experimental studies, highlights tissue- and endothelial cell–specific biomarkers that are indicative of immune dysregulation. The potential roles of neutrophils and damage-associated molecular pattern molecules at late stages of disease are discussed in the context of vascular leakage, pulmonary and renal injury, and scrub typhus pathogenesis. The Journal of Immunology, 2018, 200: 1233–1240.
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