Deciphering cytosolic antibacterial immunity: from triggering bacteriolysis to Aim2 inflammasome activation

Cel

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 bacteriolysis
ii) 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 peptide
iii) 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.

Dziedzina nauki

System finansowania

ERC-SG - ERC Starting Grant

Instytucja przyjmująca

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

Wkład UE

€ 1 404 687,60

Adres

RUE DE TOLBIAC 101
75654 Paris
Francja

Region

Ile-de-France Ile-de-France Paris

Rodzaj działalności

Research Organisations

Kontakt administracyjny

Dominique Pella (Mr.)

Kierownik naukowy

Thomas Henry (Dr.)

Linki

Kontakt z organizacją Strona internetowa

Koszt całkowity

Brak danych

Beneficjenci (1)