Type I and II interferons induce granulopoiesis and correlate with organ damage during infection-induced shock

Abstract

Abstract The mechanisms that drive pathology in infection-induced shock are not well understood. The tick-borne pathogen Ixodes ovatuserhlichia (IOE) induces severe inflammation, vascular damage, liver injury, and death. Mice that lack the receptor for type I IFN, or receptors for both type I and II IFNs, improves survival by 50–70 and 90%, respectively. IOE infection induced a significant increase in circulating granulocytes that depended on both type I and II IFNs. We also observed an IFN-dependent increase in eosinophils and basophils in the bone marrow in IOE-infected C57BL/6TA (WT). Although IOE infection induced an increase in bone marrow IL-5 and GM-CSF levels independent of IFN signaling, bone marrow concentrations of IL-3 and IL-13, both known to promote eosinophil differentiation and survival, increased in an IFNAR-dependent manner. Furthermore, we demonstrate an infection- and IFN-dependent increase of CCL3 and CCL5, two chemokines that promote eosinophil activation and migration. While bone marrow and blood eosinophils and basophils were increased, we observed a specific depletion of eosinophils in WT liver at day 7 post-IOE infection, correlating with increased cell death and severe liver pathology. In contrast, basophil frequencies were increased in IOE-infected WT mice. Additionally, Ifnar-deficient and Ifnar-Ifngr-deficient mice exhibited normal eosinophil and basophil frequencies and reduced liver inflammation, similar to uninfected mice. Together, our data reveal an IFN-driven cytokine and chemokine response that correlates with rampant granulopoiesis and mortality and provide evidence that IFN-induced eosinophil activation may contribute to vascular leak and liver damage in infection-induced shock. Supported by grants from NIH R35GM131842