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PLoS Pathog. 2017 Oct 19;13(10):e1006644. doi: 10.1371/journal.ppat.1006644. eCollection 2017 Oct.

MyD88-dependent inflammasome activation and autophagy inhibition contributes to Ehrlichia-induced liver injury and toxic shock.

Author information

1
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
2
Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, United States of America.
3
Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
4
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
5
Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

Abstract

Severe hepatic inflammation is a common cause of acute liver injury following systemic infection with Ehrlichia, obligate Gram-negative intracellular bacteria that lack lipopolysaccharide (LPS). We have previously shown that type I IFN (IFN-I) and inflammasome activation are key host-pathogenic mediators that promote excessive inflammation and liver damage following fatal Ehrlichia infection. However, the underlying signals and mechanisms that regulate protective immunity and immunopathology during Ehrlichia infection are not well understood. To address this issue, we compared susceptibility to lethal Ixodes ovatus Ehrlichia (IOE) infection between wild type (WT) and MyD88-deficient (MyD88-/-) mice. We show here that MyD88-/- mice exhibited decreased inflammasome activation, attenuated liver injury, and were more resistant to lethal infection than WT mice, despite suppressed protective immunity and increased bacterial burden in the liver. MyD88-dependent inflammasome activation was also dependent on activation of the metabolic checkpoint kinase mammalian target of rapamycin complex 1 (mTORC1), inhibition of autophagic flux, and defective mitophagy in macrophages. Blocking mTORC1 signaling in infected WT mice and primary macrophages enhanced bacterial replication and attenuated inflammasome activation, suggesting autophagy promotes bacterial replication while inhibiting inflammasome activation. Finally, our data suggest TLR9 and IFN-I are upstream signaling mechanisms triggering MyD88-mediated mTORC1 and inflammasome activation in macrophages following Ehrlichia infection. This study reveals that Ehrlichia-induced liver injury and toxic shock are mediated by MyD88-dependent inflammasome activation and autophagy inhibition.

PMID:
29049365
PMCID:
PMC5663626
DOI:
10.1371/journal.ppat.1006644
[Indexed for MEDLINE]
Free PMC Article

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