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

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.

Global cellular changes induced by Legionella pneumophila infection of bone marrow-derived macrophages

“…Therefore, one could speculate that Naip5 A/J provides susceptibility to Legionella infection by altering the cyclin system, which in turn affects apoptosis (Xaus et al 2001). In agreement with our findings, intracellular survival of Legionella in macrophages has been previously reported to involve modulation of apoptosis (Abdelaziz et al 2010;Nogueira et al 2009). …”

MAVS Promotes Inflammasome Activation by Targeting ASC for K63-Linked Ubiquitination via the E3 Ligase TRAF3

“…In this study, we found the expression of ASC, but not NLRP3, was controlled by MAVS-TRAF3 signaling axis, because deficiency of MAVS results in almost complete depletion of ASC protein levels with unchanged NLRP3 expression. Legionella pneumophila has been shown to block the formation of inflammasome complexes by interfering with the transcription of gene-encoding ASC and preventing ASC expression (34,35). ASC is considered the key to caspase-1 activation within the inflammasome in response to almost all upstream triggers known to induce maturation of IL-1b.…”

Modulation of Inflammasome Pathways by Bacterial and Viral Pathogens

“…The Nlrc4 inflammasome restricts Legionella growth in in vitro-cultured macrophages and in the lungs of infected mice (39,40). This pathogen interferes with the transcription upregulation of the inflammasome adaptor ASC to safeguard its proliferation in human monocytes (41). F. tularensis makes use of the putative lipid II flippase mviN to dampen activation of the AIM2 inflammasome (42).…”