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Deciphering the host and microbial grounds that license inflammasome-mediated execution

Project description

Shedding new light on innate immunity

All the functions of inflammasomes in the innate immune response are not all well known. As intracellular multi-protein complexes, inflammasomes play essential functions in immunity against microbial pathogens. The EU-funded INFLAME project will identify and characterise new host interferon-inducible factors that mediate microbial sensing by the inflammasomes. It will also uncover new non-canonical functions of inflammasome-derived proteases and gasdermins. The project will combine innovative technologies in biochemistry, molecular and cell biology, and immunology in various in vitro and in vivo models. Based on the unprecedented coupling of the CRISPR-Cas9 technology to automated visual high-throughput screening, it will develop an unbiased genome-wide search for novel effectors. The results will assist the development of host-directed therapies for auto-inflammatory disorders and infectious diseases.

Objective

Inflammasomes are intracellular multi-protein complexes that play essential functions in immunity against microbial pathogens. Upon microbial sensing, inflammasomes induce protease caspase-1-dependent maturation and release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 as well as gasdermin-D-dependent cell necrosis, namely pyroptosis. While both pyroptosis and IL-1β/IL-18 release play key parts in controlling microbial infections, the host-regulated pathways that promote detection of microbial ligands by cytosolic inflammasome-forming sensors and the non-canonical functions of inflammasome-derived components, remain to be fully characterized.

Building on my expertise in the field of inflammasome regulators during microbial infections, I propose to study several key, yet unexplored aspects of the functions of inflammasomes in immunity from different angles. In particular, I propose to 1/ identify and characterize new host interferon-inducible factors that mediate microbial sensing by the inflammasomes, and 2/ unravel new non-canonical functions of inflammasome-derived proteases and gasdermins.

To address these issues, I will use a combination of state-of-the-art and innovative technologies in biochemistry, molecular and cell biology, and immunology in various in vitro and in vivo models. For example, I propose to develop an unbiased genome-wide search for novel effectors involved in inflammasome activation based on the unprecedented coupling of the CRISPR-Cas9 technology to automated visual high-throughput screening.

This multidisciplinary proposal will provide breakthroughs in the field of microbial pathogens detection by the host immune system, and will nucleate entirely novel immune paradigms on microbial sensing by new unsuspected host cytosolic proteins, namely the gasdermins. The results of this project will also provide strong bases for building innovative host-directed therapies for auto-inflammatory disorders and infectious diseases.

Host institution

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Net EU contribution
€ 1 498 799,00
Address
RUE MICHEL ANGE 3
75794 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
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Total cost
€ 1 498 799,00

Beneficiaries (1)