ABSTRACTHuman monocytic ehrlichiosis (HME) is caused by a tick-borne obligate intracellular pathogen of the orderRickettsiales. HME disease can range from mild to a fatal, toxic shock-like syndrome, yet the mechanisms regulating pathogenesis are not well understood. We define a central role for type I interferons (alpha interferon [IFN-α] and IFN-β) in severe disease in a mouse model of fatal ehrlichiosis caused byIxodes ovatusEhrlichia(IOE). IFN-α and IFN-β were induced by IOE infection but not in response to a less virulent strain,Ehrlichia muris. The major sources of type I IFNs during IOE infection were plasmacytoid dendritic cells and monocytes. Mice lacking the receptor for type I IFNs (Ifnardeficient) or neutralization of IFN-α and IFN-β resulted in a reduced bacterial burden.Ifnar-deficient mice exhibited significantly increased survival after IOE infection, relative to that of wild-type (WT) mice, that correlated with increased type II IFN (IFN-γ) production. Pathogen-specific antibody responses were also elevated inIfnar-deficient mice, and this required IFN-γ. Remarkably, increased IFN-γ and IgM were not essential for protection in the absence of type I IFN signaling. The direct effect of type I IFNs on hematopoietic and nonhematopoietic cells was evaluated in bone marrow chimeric mice. We observed that chimeric mice containingIfnar-deficient hematopoietic cells succumbed to infection early, whereasIfnar-deficient mice containing WT hematopoietic cells exhibited increased survival, despite having a higher bacterial burden. These data demonstrate that IFN-α receptor signaling in nonhematopoietic cells is important for pathogenesis. Thus, type I IFNs are induced during a rickettsial infectionin vivoand promote severe disease.
Type I Interferons Promote Severe Disease in a Mouse Model of Lethal Ehrlichiosis