Type I interferon signaling is required for activation of the inflammasome during Francisella infection.
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 essential for caspase-1 activation, inflammasome-mediated cell death, and release of IL-1beta and -18. Extensive type I IFN-dependent cell death resulting in macrophage depletion occurs in vivo during F. novicida infection. Type I IFN is also necessary for inflammasome activation in response to cytosolic Listeria monocytogenes but not vacuole-localized Salmonella enterica serovar Typhimurium or extracellular adenosine triphosphate. These results show the specific connection between type I IFN signaling and inflammasome activation, which are two sequential events triggered by the recognition of cytosolic bacteria. To our knowledge, this is the first example of the positive regulation of inflammasome activation. This connection underscores the importance of the cytosolic recognition of pathogens and highlights how multiple innate immunity pathways interact before commitment to critical host responses.
Henry
Thomas
T
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
Brotcke
Anna
A
Weiss
David S
DS
Thompson
Lucinda J
LJ
Monack
Denise M
DM
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D003600:Cytosol / Q000276:immunology / Q000382:microbiology; D005603:Francisella; D016905:Gram-Negative Bacterial Infections / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*
D018836:Inflammation Mediators; D007370:Interferon Type I