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-1b, IL-1a, and type I interferon (IFN-I). Wild-type and Casp1 À/À mice were highly susceptible to fatal ehrlichiosis, had overwhelming infection, and developed extensive tissue injury. Nlrp3 À/À mice effectively cleared ehrlichiae, but displayed acute mortality and developed liver injury similar to wild-type mice. By contrast, Ifnar1 À/À mice were highly resistant to fatal disease and had lower bacterial burden, attenuated pathology, and prolonged survival. Ifnar1 À/À mice also had improved protective immune responses mediated by IFN-g and CD4 þ Th1 and natural killer T cells, with lower IL-10 secretion by T cells. Importantly, heightened resistance of Ifnar1 À/À mice correlated with improved autophagosome processing, and attenuated noncanonical inflammasome activation indicated by decreased activation of caspase-11 and decreased IL-1b, 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 þ T cells and natural killer T-cell responses against ehrlichiae. (Am J Pathol 2015, 185: 446e461; http://dx.

Interferon-Alpha Promotes Th1 Response and Epithelial Apoptosis via Inflammasome Activation in Human Intestinal Mucosa

“…It should be noted that the human normal intestinal mucosa is a reservoir of pro–caspase-1 and pro-IL18, present in epithelial cells and in some lamina propria macrophages, which can be activated rapidly and can initiate a Th1 response 16 . In addition, in recent reports, using in vitro models or mouse models, including genetically engineered mice, type I IFN has emerged as a regulator of inflammasome activation, although the exact mechanism is not understood 38, 39, 40…”

The Rickettsial Ankyrin Repeat Protein 2 Is a Type IV Secreted Effector That Associates with the Endoplasmic Reticulum

“…Due to high flexibility and sequence degeneracy, ankyrin domains allow for interaction with a diversity of cellular targets (10). Each ARP characterized from the intracellular pathogens Anaplasma phagocytophilum, Ehrlichia chaffeensis, Legionella pneumophila, and Orientia tsutsugamushi performs a unique task, such as directly influencing gene transcription, hijacking vesicular trafficking, interrupting signaling, or disrupting organelles (11)(12)(13)(14)(15)(16)(17). Despite the occurrence of ARPs in all rickettsial genomes, their roles during rickettsial pathogenesis remain unstudied.…”

For Whom the Bell Tolls (and Nods): Spit-acular Saliva

“…In agreement with this, a 2015 study published by Yang et al . suggests that activation of the non-canonical inflammasome, mediated by caspase-11 activation, contributes to fatal ehrlichiosis which is ultimately governed by type I interferon [61]. In this report nlrp3 −/− mice cleared the bacteria more efficiently than wild type mice, although they succumbed to infection at the same rate.…”

“…The pathology associated with certain diseases can be directly attributed to the host immune response, rather than the pathogen itself. For example, it is well known that some Lyme disease patients can have autoimmune symptoms, such as treatment-resistant Lyme arthritis [76,77] and, as discussed earlier in this review, inflammation resulting from Nod2 signaling in Ehrlichiosis can cause toxic shock syndrome (while TLR2 responses are protective) [61]. Potential to combat these diseases with salivary molecules exists if they can skew an immune reaction from a pathological outcome to a protective response.…”

“…Mice deficient for the interferon α/β receptor, ifnar , were highly resistant to fatal ehrlichiosis, had less liver damage, lower bacterial burdens and prolonged survival. The mechanistic understanding for how IFN-I activates the non-canonical inflammasome remains to be determined, as assays were limited to cytokine measurement [61]. Interestingly, these results imply that there is yet another uncharacterized PAMP that activates the NLR signaling pathway, as E. chaffeensis does not have LPS or peptidoglycan [27].…”