title: Canonical Inflammasomes Drive IFN-γ to Prime Caspase-11 in Defense against a Cytosol-Invasive Bacterium.
abstract: The inflammatory caspases 1 and 11 are activated in response to different agonists and act independently to induce pyroptosis. In the context of IL-1β/IL-18 secretion, however, in vitro studies indicate that caspase-11 acts upstream of NLRP3 and caspase-1. By contrast, studying infection in vivo by the cytosol-invasive bacterium Burkholderia thailandensis, we find that caspase-1 activity is required upstream of caspase-11 to control infection. Caspase-1-activated IL-18 induces IFN-γ to prime caspase-11 and rapidly clear B. thailandensis infection. In the absence of IL-18, bacterial burdens persist, eventually triggering other signals that induce IFN-γ. Whereas IFN-γ was essential, endogenous type I interferons were insufficient to prime caspase-11. Although mice transgenic for caspase-4, the human ortholog of caspase-11, cleared B. thailandensis in vivo, they did not strictly require IFN-γ priming. Thus, caspase-1 provides priming signals upstream of caspase-11 but not caspase-4 during murine defense against a cytosol-invasive bacterium.
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors: Youssef
authors: Y
authors: Aachoui
authors: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Yuji
authors: Y
authors: Kajiwara
authors: Center for Infectious Disease Research, Seattle, WA 98109, USA.
authors: Irina A
authors: IA
authors: Leaf
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors: Dat
authors: D
authors: Mao
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors: Jenny P-Y
authors: JP
authors: Ting
authors: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Jörn
authors: J
authors: Coers
authors: Center for Infectious Disease Research, Seattle, WA 98109, USA.
authors: Alan
authors: A
authors: Aderem
authors: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Joseph D
authors: JD
authors: Buxbaum
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Electronic address: emiao@med.unc.edu.
authors: Edward A
authors: EA
authors: Miao
mesh_terms: D000818:Animals; D019117:Burkholderia / Q000276:immunology*; D020170:Caspase 1 / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D053471:Caspases, Initiator / Q000378:metabolism; D003600:Cytosol / Q000382:microbiology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction
chemical_list: D058847:Inflammasomes; D020382:Interleukin-18; D007371:Interferon-gamma; C093516:CASP4 protein, human; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1