The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nat Immunol

Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Nature Immunology (Impact Factor: 20). 03/2010; 11(5):385-93. DOI: 10.1038/ni.1859
Source: PubMed


Francisella tularensis, the causative agent of tularemia, infects host macrophages, which triggers production of the proinflammatory cytokines interleukin 1beta (IL-1beta) and IL-18. We elucidate here how host macrophages recognize F. tularensis and elicit this proinflammatory response. Using mice deficient in the DNA-sensing inflammasome component AIM2, we demonstrate here that AIM2 is required for sensing F. tularensis. AIM2-deficient mice were extremely susceptible to F. tularensis infection, with greater mortality and bacterial burden than that of wild-type mice. Caspase-1 activation, IL-1beta secretion and cell death were absent in Aim2(-/-) macrophages in response to F. tularensis infection or the presence of cytoplasmic DNA. Our study identifies AIM2 as a crucial sensor of F. tularensis infection and provides genetic proof of its critical role in host innate immunity to intracellular pathogens.

Download full-text


Available from: Carlisle P Landel
  • Source
    • "concentration inhibits IL-1b secretion and pro-IL-1b translation induced by M. bovis in THP-1 macrophages The NLRP3 and AIM2 inflammasomes are activated upon mycobacterial infection in murine macrophages, and they are both inhibited by high extracellular K ? concentrations as described by Fermandes-Alnemri et al.and Petrilli et al. (Fernandes-Alnemri et al. 2010; Petrilli et al. 2007). We found that IL-1b secretion was reduced by high extracellular K ? "

    Full-text · Dataset · Sep 2015
  • Source
    • "Therefore, these proteins can theoretically bind nucleic acids and recruit ASC to trigger the formation of an inflammasome . Indeed, AIM2 can form an inflammasome whose assembly is stimulated by recognition of cytosolic DNA of bacterial or viral origin (Fernandes-Alnemri et al. 2010; Jones et al. 2010; Rathinam et al. 2010; Sauer et al. 2010), or self-DNA from apoptotic cells (Choubey 2012; Zhang et al. 2013). Recent crystal structures of AIM2 complexed with DNA have provided particular insight into the mechanism of AIM2 inflammasome activation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammasomes are large cytosolic multiprotein complexes that assemble in response to detection of infection- or stress-associated stimuli and lead to the activation of caspase-1-mediated inflammatory responses, including cleavage and unconventional secretion of the leaderless proinflammatory cytokines IL-1β and IL-18, and initiation of an inflammatory form of cell death referred to as pyroptosis. Inflammasome activation can be induced by a wide variety of microbial pathogens and generally mediates host defense through activation of rapid inflammatory responses and restriction of pathogen replication. In addition to its role in defense against pathogens, recent studies have suggested that the inflammasome is also a critical regulator of the commensal microbiota in the intestine. Finally, inflammasomes have been widely implicated in the development and progression of various chronic diseases, such as gout, atherosclerosis, and metabolic syndrome. In this perspective, we discuss the role of inflammasomes in infectious and noninfectious inflammation and highlight areas of interest for future studies of inflammasomes in host defense and chronic disease.
    Full-text · Article · Oct 2014 · Cold Spring Harbor perspectives in biology
  • Source
    • "mROS has also been implicated in activation of the NLRP3 inflammsome (Heid et al., 2013). Others have routinely demonstrated that activation of the inflammasome by Fn in mouse cells is mediated exclusively by AIM2 and not NLRP3 (Fernandes-Alnemri et al., 2010; Atianand et al., 2011). Nevertheless, given the association of mROS with the NLRP3 inflammasome, we also assessed if NLRP3 contributed to cleavage of caspase-1 and secretion of IL-1β among Fn infected cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Activation of the inflammasome is important for the detection and clearance of cytosolic pathogens. In contrast to avirulent Francisella novicida (Fn), infection with virulent Francisella tularensis ssp tularensis does not trigger activation of the host AIM2 inflammasome. Here we show that differential activation of AIM2 following Francisella infection is due to sensitivity of each isolate to reactive oxygen species (ROS). ROS present at the outset of Fn infection contributes to activation of the AIM2 inflammasome, independent of NLRP3 and NADPH oxidase. Rather, mitochondrial ROS (mROS) is critical for Fn stimulation of the inflammasome. This study represents the first demonstration of the importance of mROS in the activation of the AIM2 inflammasome by bacteria. Our results also demonstrate that bacterial resistance to mROS is a mechanism of virulence for early evasion of detection by the host.
    Full-text · Article · Aug 2014 · Frontiers in Microbiology
Show more