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Typheffects

Towards a comprehensive functional and structural analysis of late Salmonella effector proteins
Funder: French National Research Agency (ANR)Project code: ANR-09-BLAN-0296

Typheffects

Description

Salmonellosis is one of the most common and widely distributed bacterial foodborne diseases. Since the beginning of the 1990s problems related to Salmonella have increased significantly and new concerns have been identified. Strains of Salmonella which are resistant to a range of antimicrobials, including first-choice agents for the treatment of humans, have emerged and are threatening to become a serious public health problem. To face this problem much research effort has been made in recent years towards understanding Salmonella pathogenesis and especially the interplay between this pathogen and host cells, expecting it will lead to the development of novel therapies. Salmonella pathogenicity relies on its capacity to enter and replicate inside host cells. The process of invasion results in internalization of the bacterium within a membrane-bound compartment, the vacuole. The goal of this research proposal is to understand the molecular mechanisms of Salmonella intracellular survival. More specifically we are interested in gaining further insights into the function of late Salmonella effector proteins that are translocated from the bacteria into the host and which profoundly modify the host cell biology and insure a successful infection. We propose to integrate diverse disciplines ranging from microbiology to structural biology in order to create a holistic appreciation of the Salmonella pathogenicity. This comprehensive study will involve : 1-The development of biochemical and yeast two-hybrid screens for the identification of host protein partners of late Salmonella effectors; 2-Functional and biochemical analyses of the identified protein-protein complexes; 3-The resolution of the three-dimensional structures of the effectors (or functional domains) individually or in complex with the specific host protein partners. Three partners with complementary expertises in genetics, microbiology, cell biology and structural techniques will achieve these goals. Collectively, these considerations will participate to document the molecular mechanisms by which a selection of Salmonella late effectors interact with host proteins in order to manipulate host-cell processes and are expected to lead to the definition of novel therapeutic and preventive strategies.

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