Type I Interferons Promote Severe Disease in a Mouse Model of Lethal Ehrlichiosis

Human monocytic ehrlichiosis (HME) is caused by a tick-borne obligate intracellular pathogen of the order Rickettsiales. 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-alpha] and IFN-beta) in severe disease in a mouse model of fatal ehrlichiosis caused by Ixodes ovatus Ehrlichia (IOE). IFN-alpha and IFN-beta 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 (Ifnar deficient) or neutralization of IFN-alpha and IFN-beta 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-gamma) production. Pathogen-specific antibody responses were also elevated in Ifnar-deficient mice, and this required IFN-gamma. Remarkably, increased IFN-alpha 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 containing Ifnar-deficient hematopoietic cells succumbed to infection early, whereas Ifnar-deficient mice containing WT hematopoietic cells exhibited increased survival, despite having a higher bacterial burden. These data demonstrate that IFN-alpha receptor signaling in nonhematopoietic cells is important for pathogenesis. Thus, type I IFNs are induced during a rickettsial infection in vivo and promote severe disease.