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Inflammasome-mediated antagonism of type I interferon enhances Rickettsia pathogenesis.

ABSTRACT: The innate immune system fights infection with inflammasomes and interferons. Facultative bacterial pathogens that inhabit the host cytosol avoid inflammasomes1-6 and are often insensitive to type I interferons (IFN-I), but are restricted by IFN-?7-11. However, it remains unclear how obligate cytosolic bacterial pathogens, including Rickettsia species, interact with innate immunity. Here, we report that the human pathogen Rickettsia parkeri is sensitive to IFN-I and benefits from inflammasome-mediated host cell death that antagonizes IFN-I. R. parkeri-induced cell death requires the cytosolic lipopolysaccharide (LPS) receptor caspase-11 and antagonizes IFN-I production mediated by the DNA sensor cGAS. The restrictive effects of IFN-I require the interferon regulatory factor IRF5, which upregulates genes encoding guanylate-binding proteins (GBPs) and inducible nitric oxide synthase (iNOS), which we found to inhibit R. parkeri. Mice lacking both IFN-I and IFN-? receptors succumb to R. parkeri, revealing critical and overlapping roles for these cytokines in vivo. The interactions of R. parkeri with inflammasomes and interferons are similar to those of viruses, which can exploit the inflammasome to avoid IFN-I12, are restricted by IFN-I via IRF513,14, and are controlled by IFN-I and IFN-? in vivo15-17. Our results suggest that the innate immune response to an obligate cytosolic bacterial pathogen lies at the intersection of antibacterial and antiviral responses.

SUBMITTER: Burke TP

PROVIDER: S-EPMC7239376 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Inflammasome-mediated antagonism of type I interferon enhances Rickettsia pathogenesis.

Burke Thomas P TP Engström Patrik P Chavez Roberto A RA Fonbuena Joshua A JA Vance Russell E RE Welch Matthew D MD

Nature microbiology 20200302 5

The innate immune system fights infection with inflammasomes and interferons. Facultative bacterial pathogens that inhabit the host cytosol avoid inflammasomes<sup>1-6</sup> and are often insensitive to type I interferons (IFN-I), but are restricted by IFN-γ<sup>7-11</sup>. However, it remains unclear how obligate cytosolic bacterial pathogens, including Rickettsia species, interact with innate immunity. Here, we report that the human pathogen Rickettsia parkeri is sensitive to IFN-I and benefit ...[more]

PMID: 32123346

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Inflammasome-mediated antagonism of type I interferon enhances Rickettsia pathogenesis.

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Inflammasome-mediated antagonism of type I interferon enhances Rickettsia pathogenesis.

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