Microbial toxins in host pathogen interactions

Previous activities

Bacterial protein AB toxins confer upon pathogenic bacteria individual specific virulence properties leading to distinctive pathophysiological effects. Protein toxins, such as neurotoxins and those targeting Rho GTPases have also proven being extremely useful tools to study cell biology processes and cell signaling pathways of broad importance and implicated in a large number of human diseases, such as mental disorders and cancer.
Our team investigates the cellular mode of action of microbial toxins mainly through the study of CNF1 of uropathogenic Escherichia coli, EDIN exotoxins of Staphylococcus aureus and the anthrax toxin of Bacillus anthracis. These pathogens are responsible for high cost and/or severe infections. One of the main topics 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, Rho GTPases and cAMP flux, which are master regulators of host cell homeostasis notably actin cytoskeleton and consequently endothelium barrier function. We have shown that the targeting of these host regulators of the actin cytoskeleton allows bacteria to invade their host and overwhelm host defenses. These last years we have 1) discovered a new cellular mechanism of formation of transcellular tunnels in endothelial cells induced by EDIN of S. aureus and adenylate cyclase toxins, such as the edema toxin of B. anthracis. 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 follow up of our initial discovery of a cellular mode of regulation of Rho proteins by the ubiquitin and proteasome system. Most importantly, this allowed us to establish recently that the E3 ubiquitin-ligase activity of HACE1, a major tumor suppressor, targets activated Rac1 for degradation.

 

Team Publications