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


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
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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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    • "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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    • "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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