Scientific topics
Keywords
Patrick Munro PhD Microbiology
Course and current status
INSERM U95, C3M, team 6 (http://www.unice.fr/c3m/FR/Equipe6.html).
Scientific summary
Cellular response to bacterial infection : bacterial toxins and Rho GTPases.
Our team investigates the mode of action of microbial toxins mainly through the study of CNF1 toxin of uropathogenic Escherichia coli, EDIN exotoxins of Staphylococcus aureus and the Anthrax toxins of Bacillus anthracis. These pathogens are responsible for high cost and/or severe infections. One of the main axis of our work is to define the functions of these toxins during the course of the infection in relation to their cytotoxicity. Noteworthy, our studies are focused on a group of toxins targeting host MAPK kinases and Rho GTPases, two families of master regulators of host cell homeostasis notably actin cytoskeleton and consequently endothelium barrier function. Importantly, we have shown that the targeting of these host regulators of the actin cytoskeleton allows bacteria to invade their host and overwhelm host defences. These last four years we have reported four important findings. Two aspects correspond to the hijacking of endothelium actin cytoskeleton regulation and thus barrier function by bacterial pathogens targeting Rho GTPases and MAPK kinases. 1) We have discovered a new cellular mechanism of formation of transcellular tunnels in endothelial cells by EDIN of S. aureus and determined the importance of this phenomenon in S. aureus dissemination by a haematogenous route. 2) We have further deciphered the mode of action of the lethal factor component of the anthrax toxin on the endothelium by determining its major role in hijacking host transcription to induce actin cable formation strikingly in absence of direct activation of RhoA. 3) The third aspect corresponds to the determination of the pathway of Rac ubiquitination and regulation of Rac1. 4) Finally we have demonstrated that activation of Rac1 by CNF1 allows pathogen internalization by corrupting Tollip/Tom1/Clathrin components of the endocytic machinery.
