Biomedical research institute
     

    Project 1

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    Mechanism of bacterial invasion in epithelial cells


    Principal Investigator : Cécile Arrieumerlou

    cecile.arrieumerlou@inserm.fr
    Phone : 01 40 51 64 76


    Objective


    Epithelial cells line major cavities of the body and constitute the first cellular gates for various pathogenic bacteria and viruses. The human pathogen Shigella flexneri invades intestinal epithelial cells and uses them as replication niche. Although several host/pathogen molecular interactions involved in this process are known, our understanding of the mechanism of S. flexneri entry into these cells remains limited. Our objective is to discover new cellular factors involved in S. flexneri entry and characterize them at the molecular level to propose new drug targets for treatment.

     

    Research interests


    S. flexneri
    uptake into intestinal epithelial cells is a multi-step process that requires the translocation of bacterial effector proteins into the cytoplasm of target cells via a sophisticated nano syringe-like device, the type III secretion apparatus. Upon contact between the tip complex of the type III apparatus and host cell receptors localized in lipid rafts, the secreted proteins IpaB and IpaC insert into the plasma membrane and form a pore through which several effectors translocate. Among these, the bacterial proteins IpaA, IpaB, IpaC, IpgB1, IpgB2, IpgD and VirA act synergistically to induce membrane ruffling and bacterial engulfment.


    Although several host factors involved in S. flexneri entry are known, the characterization of the cellular pathways involved in this process remains limited. As bacteria rely on these factors to enter cells, they potentially constitute interesting targets for treatment. In order to address this point, our lab undertook the systematic identification of the host proteins required for S. flexneri uptake by performing a genome wide RNAi screen. These proteins are collectively defined as the infectome. This work was initiated in the frame of InfectX, a consortium of 11 experimental and modeling research groups (http://www.infectx.ch/). The aim of the consortium is to identify the components of the human infectome for a set of important bacterial and viral pathogens (S. flexneri, Listeria monocytogenes, Brucella abortus, Bartonella henselae, Salmonella typhimurium, adenovirus, rhinovirus and vaccinia virus) and to develop new mathematical and computational methods with predictive power to reconstruct key signaling pathways controlling pathogen entry into human cells, and facilitate the identification of targets for anti-infective drugs.

     

    Financial support


    This project is supported by the Swiss National fund, InfectX and the INSERM.