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-α] and IFN-β) in severe disease in a mouse model of fatal ehrlichiosis caused by Ixodes ovatus Ehrlichia (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 (Ifnar deficient) 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 in Ifnar-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 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-α 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.
Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
Yubin
Y
Zhang
Vinh
V
Thai
Amanda
A
McCabe
Maura
M
Jones
Katherine C
KC
MacNamara
D000704:Analysis of Variance; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D004195:Disease Models, Animal; D004536:Ehrlichia / Q000472:pathogenicity*; D016873:Ehrlichiosis / Q000276:immunology*; D007075:Immunoglobulin M / Q000502:physiology; D007370:Interferon Type I / Q000502:physiology*; D016898:Interferon-alpha / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL
D007075:Immunoglobulin M; D007370:Interferon Type I; D016898:Interferon-alpha; D007371:Interferon-gamma