A novel role for cell autonomous immunity in inflammasome activation during Gram- negative bacterial infections
Third-party funded project
Project title A novel role for cell autonomous immunity in inflammasome activation during Gram- negative bacterial infections
Principal Investigator(s) Broz, Petr
Project Members Dreier, Roland
Organisation / Research unit Departement Biozentrum / Infection Biology (Broz)
Project start 01.04.2014
Probable end 01.04.2019
Status Completed

Recognizing the presence of invading pathogens is key to mounting an effective immune response1. The mammalian innate immune system employs several classes of germline-encoded pattern recognition receptors (PRRs) to monitor the extracellular and intracellular compartments of host cells for signs of infection. A subset of these, the NOD-like receptors, detects the presence of pathogens in the cytoplasm and assembles so-called inflammasome complexes, which activate the mammalian cysteine protease caspase-1. Active caspase-1 is a key determinant of inflammation, since it promotes the secretion of pro-inflammaotory cytokines like interleukin (IL)-1b and IL-18, and induces an inflammatory cell death called “pyroptosis”1.

Recently, a novel non-canonical inflammasome pathway has been identified which leads to the activation of caspase-112. We and others have shown that this pathway specifically responds to intracellular Gram-negative bacteria but not to Gram-positive pathogens3,4. Consistently, caspase-11 has been shown to promote lethality in a murine model of Lipopolysaccharaide (LPS)-induced septic shock 2. In line with these observations, it has been recently reported that cytoplasmic LPS is most likely the trigger of the non-canonical inflammasome5.

Interestingly, activation of caspase-11 also requires preceding production of type-I-interferon, indicating an important role for one or several interferon-induced genes in caspase-11 activation 3,4. We have recently carried out a siRNA screen with the goal of defining factors necessary for caspase-11 activation. This led to the identification of a family of interferon-inducible GTPases that control a number of bacteriocidal mechanisms and restrict growth of pathogens in cells6. Based on these data, we propose a novel and original hypothesis in that the cytosolic detection of bacteria by PRRs requires preceding killing of bacteria by interferon-induced cell autonomous defense mechanisms, thus establishing a so-far unrecognized link between these distinct arms of innate immunity.

Financed by University of Basel

Published results ()

  ID Autor(en) Titel ISSN / ISBN Erschienen in Art der Publikation
2471108  Meunier, Etienne; Dick, Mathias S.; Dreier, Roland F.; Schürmann, Nura; Kenzelmann Broz, Daniela; Warming, Søren; Roose-Girma, Merone; Bumann, Dirk; Kayagaki, Nobuhiko; Takeda, Kiyoshi; Yamamoto, Masahiro; Broz, Petr  Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases  0028-0836 ; 1476-4687  Nature  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
2834776  Meunier, Etienne; Broz, Petr  Interferon-induced guanylate-binding proteins promote cytosolic lipopolysaccharide detection by caspase-11  1044-5498  DNA and cell biology  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 

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