ROSCop

To fight against Salmonella, immune cells have a powerful antibacterial arsenal including the mobilization of copper (Cu), an essential transition metal which is toxic at high concentrations. Immune cells also relie on their ability to produce Reactive Oxygen Species (ROS) and Reactive Chlorine Species (RCS) which damage and kill invading bacteria. Thus, Salmonella enterica has evolved defense mechanisms to scavenge or degrade these oxidants. Cu activates the expression of several genes, among which membrane exporters and enzymes involved in Cu homeostasis. In addition, we have recently identified N-chlorotaurine (N-ChT) - a molecule formed by the combination of HOCl and taurine - as a major activator of the Cpx system, dedicated to protein quality control in the bacterial envelope. Our preliminary data show that the expression of cueP, encoding a periplasmic metallochaperone, is under the control of two simultaneous stimuli: Cu and N-ChT. In the present project, we aim to elucidate the timing and spatial coexistence of Cu and N-ChT dual stress within the host environment. Using multi-omics approaches, the first work-package (WP1) will aim at identifying genes involved in resistance mechanisms to Cu and N-ChT dual stress. WP2 will consist of mice infection using Salmonella strains carrying dedicated fluorescent reporters to find out when and where Cu and N-ChT are encountered by Salmonella during the infectious process. WP3 will enable to decipher how host cells identified in WP2 orchestrate the concomitant Cu/N-ChT stress release and to assess the level of stress experienced by Salmonella within these host cells. This project will enable us to gain a better understanding of molecular strategies used by the host to eradicate pathogens, as well as the defense mechanisms used by Salmonella to survive in this environment.