Inflammasome-mediated antagonism of type I interferon enhances Rickettsia pathogenesis
- 1 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Microbiology
- Vol. 5 (5), 688-696
- https://doi.org/10.1038/s41564-020-0673-5
Abstract
The innate immune system fights infection with inflammasomes and interferons. Facultative bacterial pathogens that inhabit the host cytosol avoid inflammasomes1,2,3,4,5,6 and are often insensitive to type I interferons (IFN-I), but are restricted by IFN-γ7,8,9,10,11. 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-γ 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-γ in vivo15,16,17. Our results suggest that the innate immune response to an obligate cytosolic bacterial pathogen lies at the intersection of antibacterial and antiviral responses.Keywords
Funding Information
- Svenska Sällskapet för Medicinsk Forskning
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (2T34GM008612-24)
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (R37 AI075039, P01 AI063302, R01 AI109044, R21 AI109270, R21 AI138550)
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases
- Howard Hughes Medical Institute
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases
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