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Type I interferon signaling is required for activation of the inflammasome during Francisella infection

ABSTRACT: Francisella are pathogenic bacteria whose virulence is linked to their ability to replicate within the host cell cytosol. Entry into the macrophage cytosol activates a host protective multimolecular complex called the inflammasome to release the proinflammatory cytokines IL-1 and IL-18 and trigger caspase-1 dependent cell death. Here we show that cytosolic Francisella induce a type I interferon (IFN) response that is essential for caspase-1 activation, inflammasome mediated cell death, and release of IL-1 and IL-18. Extensive type I IFN dependent cell death resulting in macrophage depletion occurs in vivo during Francisella infection. Type I IFN is also necessary for inflammasome activation in response to cytosolic Listeria but not vacuole localized Salmonella or extracellular ATP. These results show the specific connection between type I IFN signaling and inflammasome activation, two sequential events triggered by recognition of cytosolic bacteria. To our knowledge, this is the first example of positive regulation of inflammasome activation. This connection underscores the importance of cytosolic recognition of pathogens and highlights how multiple innate immunity pathways interact before commitment to critical host responses. Keywords: murine macrophage response to Francisella tularensis subspecies novicida infection

ORGANISM(S): Mus musculus

PROVIDER: GSE7684 | GEO | 2007/05/23

SECONDARY ACCESSION(S): PRJNA99435

REPOSITORIES: GEO

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Project description:The cellular stress response plays a vital role in regulating homeostasis by modulating cell survival and death. Stress granules (referred to as SGs) are cytoplasmic compartments that allow cells to survive various stressors. Defects in SG assembly and disassembly have been found to play important roles in neurodegenerative diseases, antiviral responses and cancer1–5. Inflammasomes are multi-protein heteromeric complexes that sense intracellular pathogen- and damage-associated molecular patterns and assemble into cytosolic compartments called ASC specks to facilitate caspase-1 (CASP1) activation. This activation of inflammasomes induces secretion of the leaderless proinflammatory cytokines IL-1β and IL-18 and also drives cell fate towards pyroptosis, a form of programmed inflammatory cell death that plays major role in health and disease6–12. Cellular stress sensing can trigger both SGs and inflammasomes; however, they drive contrasting cell fate decisions during stress conditions. Crosstalk between SGs and inflammasomes to decide cell fate has not been well studied. Here we show that the induction of SGs specifically inhibits NLRP3 inflammasome activation, ASC speck formation and pyroptosis. The SG protein DDX3X interacts with NLRP3 to drive inflammasome activation in the absence of SGs. Assembly of SGs leads to the sequestration of DDX3X to inhibit NLRP3 inflammasome function. SGs and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell fate decisions under stress conditions. Induction of SGs or loss of DDX3X in the myeloid compartment leads to decreased production of inflammasome-dependent cytokines in vivo. Our findings suggest that macrophages utilize DDX3X availability to interpret stress signals and choose between pro-survival SGs and pyroptotic ASC specks. Together, our data show the role of DDX3X in driving NLRP3 inflammasome and SG assembly, informing a new rheostat-like mechanistic paradigm for regulating live or die cell fate decisions under stress conditions.

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Type I interferon signaling is required for activation of the inflammasome during Francisella infection

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