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 inte...

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Bibliographic Details
Published in:Infection and immunity 2014-04, Vol.82 (4), p.1698-1709
Main Authors: Zhang, Yubin, Thai, Vinh, McCabe, Amanda, Jones, Maura, MacNamara, Katherine C
Format: Article
Language:English
Subjects:
Analysis of Variance
Animals
CD8-Positive T-Lymphocytes - metabolism
Disease Models, Animal
Ehrlichia - pathogenicity
Ehrlichia muris
Ehrlichiosis - immunology
Host Response and Inflammation
Immunoglobulin M - physiology
Interferon Type I - physiology
Interferon-alpha - physiology
Interferon-gamma - physiology
Ixodes ovatus
Mice
Mice, Inbred C57BL
Rickettsiales
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Summary: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.
ISSN:0019-9567
1098-5522
DOI:10.1128/IAI.01564-13