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Inflammasome-mediated antagonism of type I interferon enhances Rickettsia pathogenesis

Thomas P. Burke, Patrik Engström, Roberto A. Chavez, Joshua A. Fonbuena, Russell E. Vance, View ORCID ProfileMatthew D. Welch
doi: https://doi.org/10.1101/697573
Thomas P. Burke
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720 USA
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  • For correspondence: tburke@berkeley.edu welch@berkeley.edu
Patrik Engström
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720 USA
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Roberto A. Chavez
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720 USA
2Howard Hughes Medical Institute
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Joshua A. Fonbuena
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720 USA
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Russell E. Vance
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720 USA
2Howard Hughes Medical Institute
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Matthew D. Welch
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720 USA
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  • ORCID record for Matthew D. Welch
  • For correspondence: tburke@berkeley.edu welch@berkeley.edu
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Summary

Inflammasomes and interferons constitute two critical arms of innate immunity. Most facultative bacterial pathogens that inhabit the host cell cytosol avoid activating inflammasomes and are often resistant to killing by type I interferon (IFN-I). We report that the human pathogen Rickettsia parkeri, an obligate intracellular pathogen that resides in the cytosol, is sensitive to IFN-I. The mechanism of IFN-I-dependent restriction requires the transcription factor IRF5, which upregulates anti-rickettsial factors including guanylate-binding proteins and iNOS. However, R. parkeri curtails cGAS-dependent IFN-I production by causing caspase-11-dependent pyroptosis. In vivo, inflammasome activation antagonizes IFN-I production, enhancing R. parkeri abundance in the spleen. Mice lacking either IFN-I or IFN-γ signaling are resistant to infection, but mice lacking both rapidly succumb, revealing that both interferons are required to control R. parkeri. This study illuminates how an obligate cytosolic pathogen exploits the intrinsic trade-off between cell death and cytokine production to escape killing by innate immunity.

Highlights

  • Rickettsia killed by GBPs activates caspase-11 and GSDMD, promoting pyroptosis

  • Rickettsia exploits pyroptosis to avoid cGAS-dependent type I interferon

  • IRF5, GBPs, and iNOS contribute to controlling R. parkeri infection

  • Ifnar-/-Ifngr-/- mice succumb to infection, uncovering a mouse model to study R. parkeri

Footnotes

  • ↵3 Lead contact

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE128211

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 11, 2019.
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Inflammasome-mediated antagonism of type I interferon enhances Rickettsia pathogenesis
Thomas P. Burke, Patrik Engström, Roberto A. Chavez, Joshua A. Fonbuena, Russell E. Vance, Matthew D. Welch
bioRxiv 697573; doi: https://doi.org/10.1101/697573
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Inflammasome-mediated antagonism of type I interferon enhances Rickettsia pathogenesis
Thomas P. Burke, Patrik Engström, Roberto A. Chavez, Joshua A. Fonbuena, Russell E. Vance, Matthew D. Welch
bioRxiv 697573; doi: https://doi.org/10.1101/697573

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