The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20062665
The Journal of Experimental Medicine, Vol. 204, No. 5, 987-994
The Rockefeller University Press, 0022-1007 $30.00
© Henry et al.
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BRIEF DEFINITIVE REPORT

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

Thomas Henry, Anna Brotcke, David S. Weiss, Lucinda J. Thompson, and Denise M. Monack

Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305

CORRESPONDENCE Denise M. Monack: dmonack{at}stanford.edu

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)-1ß 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-1ß 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.

A. Brotcke and D.S. Weiss contributed equally to this paper.


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