Amer, A. et al. Regulation of Legionella phagosome maturation and infection through flagellin and host IPAF. J. Biol. Chem. 281, 35217-35223

Emory University, Atlanta, Georgia, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2006; 281(46):35217-23. DOI: 10.1074/jbc.M604933200
Source: PubMed


Legionella pneumophila is an intracellular bacterium that causes an acute form of pneumonia called Legionnaires' disease. After infection of human macrophages, the Legionella-containing phagosome (LCP) avoids fusion with the lysosome allowing intracellular replication of the bacterium. In macrophages derived from most mouse strains, the LCP is delivered to the lysosome resulting in Legionella degradation and restricted bacterial growth. Mouse macrophages lacking the NLR protein Ipaf or its downstream effector caspase-1 are permissive to intracellular Legionella replication. However, the mechanism by which Ipaf restricts Legionella replication is not well understood. Here we demonstrate that the presence of flagellin and a competent type IV secretion system are critical for Legionella to activate caspase-1 in macrophages. Activation of caspase-1 in response to Legionella infection also required host Ipaf, but not TLR5. In the absence of Ipaf or caspase-1 activation, the LCP acquired endoplasmic reticulum-derived vesicles, avoided fusion with the lysosome, and allowed Legionella replication. Accordingly a Legionella mutant lacking flagellin did not activate caspase-1, avoided degradation, and replicated in wild-type macrophages. The regulation of phagosome maturation by Ipaf occurred within 2 h after infection and was independent of macrophage cell death. In vivo studies confirmed that flagellin and Ipaf play an important role in the control of Legionella clearance. These results reveal that Ipaf restricts Legionella replication through the regulation of phagosome maturation, providing a novel function for NLR proteins in host defense against an intracellular bacterium.

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Available from: Nesrin Ozoren, Sep 30, 2014
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    • "Recently, it has been demonstrated that Cryopyrin, Ipaf, as well as the adaptor ASC, are required for the activation of caspase-1 in response to pathogenic components and intracellular bacteria which is TLR-independent [36] [38] [39] [130] [131] [145] [152]. "

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    • "Recently, it has been demonstrated that Cryopyrin, Ipaf, as well as the adaptor ASC, are required for the activation of caspase-1 in response to pathogenic components and intracellular bacteria which is TLR-independent [36] [38] [39] [130] [131] [145] [152]. "

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    • "Because the initiation of autophagy seems to precede the induction of pyroptosis, autophagy can be considered a pathway through which macrophages raise the threshold of contaminants necessary to result in the loss of cell by inflammatory cell death. NAIP5/NLRC4 can also restrict flagellin-competent L. pneumophila replication by promoting the delivery of L. pneumophila-containing phagosomes (LCP) to lysosomes for degradation (43, 97). In the absence of NAIP5/NLRC4/caspase-1, LCP avoids fusion with lysosomes, which allows the pathogen to exponentially replicate inside macrophages. "
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    ABSTRACT: Neuronal apoptosis inhibitory protein (NAIP)/NOD-like receptor (NLR) containing a caspase activating and recruitment domain (CARD) 4 (NLRC4) inflammasome complexes are acti-vated in response to proteins from virulent bacteria that reach the cell cytosol. Specific NAIP proteins bind to the agonists and then physically associate with NLRC4 to form an inflammasome complex able to recruit and activate pro-caspase-1. NAIP5 and NAIP6 sense flagellin, component of flagella from motile bacteria, whereas NAIP1 and NAIP2 detect needle and rod components from bacterial type III secretion systems, respectively. Active caspase-1 mediates the maturation and secretion of the pro-inflammatory cytokines, IL-1β and IL-18, and is responsible for the induction of pyroptosis, a pro-inflammatory form of cell death. In addition to these well-known effector mechanisms, novel roles have been described for NAIP/NLRC4 inflammasomes, such as phagosomal maturation, activation of inducible nitric oxide synthase, regulation of autophagy, secretion of inflammatory media-tors, antibody production, activation of T cells, among others. These effector mechanisms mediated by NAIP/NLRC4 inflammasomes have been extensively studied in the context of resistance of infections and the potential of their agonists has been exploited in therapeutic strategies to non-infectious pathologies, such as tumor protection. Thus, this review will discuss current knowledge about the activation of NAIP/NLRC4 inflammasomes and their effector mechanisms.
    Frontiers in Immunology 07/2014; 5. DOI:10.3389/fimmu.2014.00309
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