Strong Type 1, but Impaired Type 2, Immune Responses Contribute to Orientia tsutsugamushi-Induced Pathology in Mice.

Scrub typhus is a neglected, but important, tropical disease, which puts one-third of the world's population at risk. The disease is caused by Orientia tsutsugamushi, an obligately intracellular Gram-negative bacterium. Dysregulation in immune responses is known to contribute to disease pathogenesis; however, the nature and molecular basis of immune alterations are poorly defined. This study made use of a newly developed murine model of severe scrub typhus and focused on innate regulators and vascular growth factors in O. tsutsugamushi-infected liver, lungs and spleen. We found no activation or even reduction in base-line expression for multiple molecules (IL-7, IL-4, IL-13, GATA3, ROR-γt, and CXCL12) at 2, 6 and 10 days post-infection. This selective impairment in type 2-related immune responses correlated with a significant activation of the genes for IL-1β, IL-6, IL-10, TNF-α, IFN-γ, as well as CXCR3- and CXCR1-related chemokines in inflamed tissues. The elevated angiopoietin (Ang)-2 expression and Ang-2/Ang-1 ratios suggested excessive inflammation and the loss of endothelial integrity. These alterations, together with extensive recruitment of myeloperoxidase (MPO)-expressing neutrophils and the influx of CD3+ T cells, contributed to acute tissue damage and animal death. This is the first report of selective alterations in a panel of immune regulators during early O. tsutsugamushi infection in intravenously inoculated C57BL/6 mice. Our findings shed new light on the pathogenic mechanisms associated with severe scrub typhus and suggest potential targets for therapeutic investigation. Author Summary: Scrub typhus is a life-threatening disease, often displayed as severe acute febrile illness. It is caused by infection with O. tsutsugamushi, a Gram-negative intracellular bacterium. Every year, approximately one million people are infected globally, especially in the Asia-Pacific region. Mechanistic studies of host immune responses are limited, partially due to the limited availability of suitable animal models and research facilities. We demonstrated here selective suppression in innate immune regulators, but activation of inflammatory cytokines, during the first few days of O. tsutsugamushi infection in mice. Importantly, these immune alterations correlated with acute tissue damage, disease progression, and animal death. As the first report describing dysregulation in innate immune responses in a murine model of severe scrub typhus, this study improves our understanding of disease mechanisms and opens new avenues for the exploration of treatment options. [ABSTRACT FROM AUTHOR]