SPATEs promote the survival of Shigella to the plasma complement system upon hemorrhage and bacteremia

Shigella spp. are the causative agents of shigellosis, which remains a leading cause of death in children under the age of five. Shigellosis is characterized by fever and results in hemorrhagic diarrhea; in more severe cases, Shigella bacteremia has been reported. These clinical features strongly suggest that Shigella survive exposure to plasma, although this has not yet been studied at the molecular level. In this report, we confirmed in a guinea pig model of shigellosis that local hemorrhages were induced by S. flexneri 5a and S. sonnei, and we demonstrated that Shigella reached mucosal CD31+/CD34+ blood vessels during the late stages of infection and further disseminated in the bloodstream. These results confirmed the exposure of Shigella to plasma components within the hemorrhagic colonic mucosa and in the bloodstream. We demonstrated that all the tested Shigella strains survived plasma exposure in vitro, and we showed that Serine Protease Autotransporters of Enterobacteriaceae (SPATEs) are essential for Shigella dissemination within the colonic mucosa. We have confirmed that SPATEs are expressed and secreted in poorly oxygenated environments encountered by Shigella from hypoxic foci of infection to the bloodstream. We further demonstrated that SPATEs promoted Shigella survival in plasma, by cleaving complement component 3 (C3), thereby impairing complement system activation. We have shown here that the ability of Shigella to survive plasma exposure is a key factor in its virulence, both within primary foci and systemically. Significance StatementIn this study we aimed to better understand the significance of the ability of Shigella to survive plasma exposure, as we observed that non-pathogenic E. coli rapidly lysed upon exposure. Indeed, we reported that Shigella was already exposed to plasma components within the colonic mucosa, as we reported in a guinea pig model of shigellosis that hemorrhages were induced, that were associated with local diffusion of plasma components in the infected colonic mucosa. Shigella was obviously exposed to plasma during bacteremia. The ability of Shigella to survive in plasma has not been previously reported. Here we have shown, first, that Shigella was able to divide and grow in the presence of human plasma, and second, we found that SPATEs played a central role in this process by impairing with the activation of the complement system.