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. © 2014 soong et al.