Deciphering cytosolic antibacterial immunity: from triggering bacteriolysis to Aim2 inflammasome activation
Start date: Nov 1, 2012,
End date: Oct 31, 2018
Bacteria replicating within host cells either multiply in membrane-bound compartment or escape into the host cytosol. The host cytosol has long been considered as a safe haven for bacteria. However, the host cytosol is armed with an array of innate immune receptors detecting cytosolic invasion. Furthermore, the macrophage cytosol displays a bacteriolytic activity, which is inducible by IFN. Surprisingly, the molecular mechanisms of this innate immune effector response are still largely uncharacterized. A ubiquitously expressed antimicrobial peptide, ubiquicidin has been described in the macrophage cytosol. Its relevance, its connection with macrophage-specific bacteriolytic activity and with IFN, remain to be deciphered. While cytosol-adapted bacteria are largely resistant to the bactericidal activity of the macrophage, lysis of a single bacterium triggers activation of the Aim2 inflammasome. Cytosolic bacteriolysis is thus key to orchestrate inflammasome-mediated innate immune responses. We propose here to characterize the bacteriolytic effector mechanisms, the regulation of this response and of the Aim2 inflammasome by IFN in infected macrophages. We will use two complementary bacterial models: F. tularensis, a cytosol-adapted bacterium and S. typhimurium sifA mutant, a bacterium lysed in the macrophage cytosol. We will develop three synergistic approaches:i) the generation of novel tools to monitor cytosolic bacteriolysisii) hypothesis-driven investigations on the antimicrobial activity of the macrophage cytosol focusing on ubiquicidin to uncover the mechanisms of processing and targeting of this antimicrobial peptideiii) screening of IFN-inducible genes to identify novel players involved in the cytosolic bacteriolytic activity and in inflammasome regulation.We believe this project should reveal the innate immune effector mechanisms of the macrophage cytosol i.e. how the macrophage kills cytosolic bacteria and orchestrates further immune responses.
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