Unknown,Transcriptomics,Genomics,Proteomics

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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 We analyzed a series of 18 MEEBO arrays on which were hybed RNA randomly amplified from bone marrow derived macrophages infected or not with WT Francisella tularensis subspecies novicida or a the mglA mutant strain GB2.

ORGANISM(S): Mus musculus

SUBMITTER: Sajeev Batra

PROVIDER: E-GEOD-7684 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Henry Thomas T Brotcke Anna A Weiss David S DS Thompson Lucinda J LJ Monack Denise M DM

The Journal of experimental medicine 20070423 5

Francisella tularensis is a pathogenic bacterium whose virulence is linked to its 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 interleukin (IL)-1beta and -18 and trigger caspase-1-dependent cell death. In this study, we show that cytosolic F. tularensis subspecies novicida (F. novicida) induces a type I interferon (IFN) response that is essen ...[more]

PMID: 17452523

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Project description:Francisella tularensis is a Gram-negative bacterium that is highly virulent in humans, causing the disease tularemia. F. novicida is closely related to F. tularensis and exhibits high virulence in mice, but is avirulent in healthy humans. A F. novicida-specific gene cluster (FTN0451-FTN0456) encodes two proteins with diguanylate cyclase (DGC) and phosphodiesterase (PDE) domains that modulate synthesis and degradation of cyclic di-GMP (cdGMP). No DGC or PDE containing proteins are present in the F. tularensis genome. F. novicida strains lacking either the two DGC/PDE genes cdgA and cdgB or the entire gene cluster (KKF457) are defective for biofilm formation. In addition, expression of CdgB or a heterologous DGC in KKF457 stimulated F. novicida biofilms, even in a strain lacking the biofilm regulator QseB. Genetic evidence suggests that CdgA is predominantly a PDE, while CdgB is predominantly a DGC. The F. novicida qseB strain has reduced cdgA and cdgB transcript levels, demonstrating a F. novicida biofilm signaling cascade that controls cdGMP levels. Interestingly, KKF457 with elevated cdGMP levels exhibited a decrease in intramacrophage replication and virulence in mice, as well as increased growth yield and biofilm formation in vitro. Microarray analyses revealed that cdGMP stimulated the transcription of a chitinase (ChiB) known to contribute to biofilm formation. Our results indicate that elevated cdGMP in F. novicida stimulates biofilm formation and inhibits virulence. We suggest that differences in human virulence between F. novicida and F. tularensis may be due in part to the absence of cdGMP signaling in F. tularensis. A whole genome NibleGen microarray was developed for multiple Francisella subspecies, using shared probes for common genes as well as unique probes for subspecies-specific genes. Included were probes representing the F. novicida U112 genome, with a maximum of 6 probes/gene. RNA was isolated from bacteria and purified as described above. The double-strand cDNA was generated and labeled with Cy3 according to the NimbleGen Gene Expression Array protocol (www.nimblegen.com), using SuperScript Double-Stranded cDNA Synthesis Kit (Invitrogen) and the DNA Labeling Kit (NimbleGen). Microarray results were analyzed using the ArrayStar software (DNASTAR).

Dataset Information

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

Publications

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

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