Strong type 1, but impaired type 2, immune responses contribute to Orientia tsutsugamushi-induced pathology in mice.

[scrub typhus]

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 , GATA 3 , ROR-γt , and CXCL 12 ) 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 -1 β , IL -6 , IL -10 , TNF -α , IFN-γ , as well as CXCR 3 - and CXCR 1 -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 CD 3 + 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 C 5 7 BL /6 mice . Our findings shed new light on the pathogenic mechanisms associated with severe scrub typhus and suggest potential targets for therapeutic investigation .

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achondroplasia

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