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Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf

Emory University, Atlanta, Georgia, United States
Journal of Biological Chemistry (Impact Factor: 4.6). 12/2006; 281(46):35217-23. DOI: 10.1074/jbc.M604933200
Source: PubMed

ABSTRACT 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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    • "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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    • "Arrows at the end of lines represent induction, while flat bars at the end of lines represent inhibition. contribute to the control of L. pneumophila replication by enhancing fusion of the Legionella-containing vacuole (LCV) with lysosomes during infections performed at a low multiplicity of infection (MOI) (Amer et al., 2006; Fortier et al., 2007). In addition, flagellin-dependent NLRC4 signaling leads to caspase-7-mediated restriction of L. pneumophila via enhanced lysosomal degradation of the bacterium (Akhter et al., 2009). "
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    ABSTRACT: Cell death can be critical for host defense against intracellular pathogens because it eliminates a crucial replicative niche, and pro-inflammatory cell death can alert neighboring cells to the presence of pathogenic organisms and enhance downstream immune responses. Pyroptosis is a pro-inflammatory form of cell death triggered by the inflammasome, a multi-protein complex that assembles in the cytosol to activate caspase-1. Inflammasome activation by pathogens hinges upon violation of the host cell cytosol by activities such as the use of pore-forming toxins, the use of specialized secretion systems, or the cytosolic presence of the pathogen itself. Recently, a non-canonical inflammasome has been described that activates caspase-11 and also leads to pro-inflammatory cell death. Caspase-11 is activated rapidly and robustly in response to violation of the cytosol by bacterial pathogens as well. In this mini-review, we describe the canonical and non-canonical inflammasome pathways that are critical for host defense against a model intracellular bacterial pathogen that accesses the host cytosol-Legionella pneumophila.
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