期刊
NATURE MICROBIOLOGY
卷 5, 期 5, 页码 688-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41564-020-0673-5
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资金
- Foundation Olle Engkvist Byggmastare
- Swedish Society of Medical Research (SSMF)
- Sweden-America Foundation
- NIH/NIAID [R01 AI109044, R21 AI109270, R21 AI138550, AI075039, AI063302]
- NIH/National Institute of General Medical Sciences (NIGMS) [2T34GM008612-24]
The innate immune system fights infection with inflammasomes and interferons. Facultative bacterial pathogens that inhabit the host cytosol avoid inflammasomes(1-6) and are often insensitive to type I interferons (IFN-I), but are restricted by IFN-gamma(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-gamma 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-I-12, are restricted by IFN-I via IRF5(13,14), and are controlled by IFN-I and IFN-gamma in vivo(15-17). Our results suggest that the innate immune response to an obligate cytosolic bacterial pathogen lies at the intersection of antibacterial and antiviral responses. Here, Rickettsia parkeri is shown to be sensitive to type I interferons (IFN-I) and IFN-gamma and to benefit from inflammasome-mediated antagonism of IFN-I, highlighting similarities between the immune responses against this obligate cytosolic bacterial pathogen and those that target viral pathogens.
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