Apoptosis-associated Speck-like Protein (ASC) Controls Legionella pneumophila Infection in Human Monocytes

Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Center for Microbial Interface Biology and the Department of Internal Medicine, Ohio State University, Columbus, Ohio 43210, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2011; 286(5):3203-8. DOI: 10.1074/jbc.M110.197681
Source: PubMed

ABSTRACT The ability of Legionella pneumophila to cause pneumonia is determined by its capability to evade the immune system and grow within human monocytes and their derived macrophages. Human monocytes efficiently activate caspase-1 in response to Salmonella but not to L. pneumophila. The molecular mechanism for the lack of inflammasome activation during L. pneumophila infection is unknown. Evaluation of the expression of several inflammasome components in human monocytes during L. pneumophila infection revealed that the expression of the apoptosis-associated speck-like protein (ASC) and the NOD-like receptor NLRC4 are significantly down-regulated in human monocytes. Exogenous expression of ASC maintained the protein level constant during L. pneumophila infection and conveyed caspase-1 activation and restricted the growth of the pathogen. Further depletion of ASC with siRNA was accompanied with improved NF-κB activation and enhanced L. pneumophila growth. Therefore, our data demonstrate that L. pneumophila manipulates ASC levels to evade inflammasome activation and grow in human monocytes. By targeting ASC, L. pneumophila modulates the inflammasome, the apoptosome, and NF-κB pathway simultaneously.

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Available from: Mikhail A Gavrilin, Sep 27, 2015
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    • "Additionally, the expression of ASC is moderately down-regulated in infected monocytes, potentially contributing to evasion of inflammasome activation in human cells by L. pneumophila (Abdelaziz et al., 2011b). Future studies in primary MDMs and human alveolar macrophages are needed to clarify the role of the inflammasome in restricting L. pneumophila replication in human cells (Figure 2). "
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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.
    Frontiers in Cellular and Infection Microbiology 12/2013; 3:111. DOI:10.3389/fcimb.2013.00111 · 3.72 Impact Factor
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    • "The Y. pseudotuberculosis YopK proteins bind to components of the bacterial type III secretion system to inhibit their recognition by host cell inflammasome (Brodsky et al., 2010). Legionella interferes with inflammasome activation by inhibiting transcription of the important inflammasome adapter gene ASC (Abdelaziz et al., 2011). "
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    ABSTRACT: The production of IL-1β during the infection with Mycobacterium tuberculosis (Mtb) is important for successful host immune defense. In macrophages and dendritic cells the host cell inflammasome is crucial for generation of secreted IL-1β in response to Mtb infections. In these cell types Mtb infection only activates the NLRP3-inflammasome. New reports demonstrate that nitric oxide has an important function in the negative regulation of the NLRP3-inflammasome to reduce tissue damage during Mtb infections. The type I interferon, IFN-β, is induced after Mtb infections and can also suppress NLRP3-inflammasome activation. In contrast, IFN-β increases activity of the AIM2-inflammasome after infection with intracellular pathogens such as Francisella tularensis and Listeria monocytogenes. Recent results demonstrate that non-tuberculous mycobacteria but not virulent Mtb induce the AIM2-inflammasome in an IFN-β dependent matter. Indeed, Mtb inhibits AIM2-inflammasome activation via its ESX-1 secretion system. This novel immune evasion mechanism may help Mtb to allow the induction of low levels of IFN-β to suppress the NLRP3-inflammasome without activating the AIM2-inflammasome.
    Frontiers in Cellular and Infection Microbiology 10/2013; 3:62. DOI:10.3389/fcimb.2013.00062 · 3.72 Impact Factor
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    • "In addition, Legionella pneumophila can manipulate ASC levels to modulate inflammasome and NF-κB pathway activation, thus evading immune evasion and promoting growth (70). When ASC was over-expressed in cells to maintain constant levels of protein during infection, caspase-1 activation and restriction of Legionella growth resulted (70). "
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    ABSTRACT: The inflammasome is a multi-protein complex that induces maturation of inflammatory cytokines interleukin (IL)-1β and IL-18 through activation of caspase-1. Several nucleotide binding oligomerization domain-like receptor family members, including NLRP3, recognize unique microbial and danger components and play a central role in inflammasome activation. The NLRP3 inflammasome is critical for maintenance of homeostasis against pathogenic infections. However, inflammasome activation acts as a double-edged sword for various bacterial infections. When the IL-1 family of cytokines is secreted excessively, they cause tissue damage and extensive inflammatory responses that are potentially hazardous for the host. Emerging evidence has shown that diverse bacterial pathogens or their components negatively regulate inflammasome activation to escape the immune response. In this review, we discuss the current knowledge of the roles and regulation of the NLRP3 inflammasome during bacterial infections. Activation and regulation of the NLRP3 inflammasome should be tightly controlled to prevent virulence and pathology during infections. Understanding the roles and regulatory mechanisms of the NLRP3 inflammasome is essential for developing potential treatment approaches against pathogenic infections.
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