title: Type I interferon contributes to noncanonical inflammasome activation, mediates immunopathology, and impairs protective immunity during fatal infection with lipopolysaccharide-negative ehrlichiae.
abstract: Ehrlichia species are intracellular bacteria that cause fatal ehrlichiosis, mimicking toxic shock syndrome in humans and mice. Virulent ehrlichiae induce inflammasome activation leading to caspase-1 cleavage and IL-18 secretion, which contribute to development of fatal ehrlichiosis. We show that fatal infection triggers expression of inflammasome components, activates caspase-1 and caspase-11, and induces host-cell death and secretion of IL-1β, IL-1α, and type I interferon (IFN-I). Wild-type and Casp1(-/-) mice were highly susceptible to fatal ehrlichiosis, had overwhelming infection, and developed extensive tissue injury. Nlrp3(-/-) mice effectively cleared ehrlichiae, but displayed acute mortality and developed liver injury similar to wild-type mice. By contrast, Ifnar1(-/-) mice were highly resistant to fatal disease and had lower bacterial burden, attenuated pathology, and prolonged survival. Ifnar1(-/-) mice also had improved protective immune responses mediated by IFN-γ and CD4(+) Th1 and natural killer T cells, with lower IL-10 secretion by T cells. Importantly, heightened resistance of Ifnar1(-/-) mice correlated with improved autophagosome processing, and attenuated noncanonical inflammasome activation indicated by decreased activation of caspase-11 and decreased IL-1β, compared with other groups. Our findings demonstrate that IFN-I signaling promotes host susceptibility to fatal ehrlichiosis, because it mediates ehrlichia-induced immunopathology and supports bacterial replication, perhaps via activation of noncanonical inflammasomes, reduced autophagy, and suppression of protective CD4(+) T cells and natural killer T-cell responses against ehrlichiae.
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Stevenson
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Scott
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: ismailn@upmc.edu.
authors.forename: Nahed
authors.initials: N
authors.lastname: Ismail
mesh_terms: D000818:Animals; D020169:Caspases / Q000235:genetics / Q000276:immunology; D053471:Caspases, Initiator; D004536:Ehrlichia / Q000276:immunology*; D016873:Ehrlichiosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007111:Immunity, Cellular; D058847:Inflammasomes / Q000276:immunology*; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D053582:Interleukin-1alpha / Q000235:genetics; D053583:Interleukin-1beta / Q000276:immunology; D008070:Lipopolysaccharides; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: C556062:IL10 protein, mouse; C587672:IL1B protein, mouse; C508032:Ifnar1 protein, mouse; D058847:Inflammasomes; D007370:Interferon Type I; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016753:Interleukin-10; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator