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

Abstract

Shigella spp. are the causative agents of shigellosis, which remains a leading cause of death in children under the age of 5. Symptoms of shigellosis include bloody diarrhea, associated to colon hemorrhage; in more severe cases, Shigella bacteremia is induced. These clinical features indicate that Shigella are exposed and survive exposure to plasma, locally and systemically, although this has not yet been studied at a molecular level. In this report, we confirmed in a guinea pig model of shigellosis that both S. flexneri 5a and S. sonnei induced local hemorrhages and we demonstrated that Shigella reached CD31+/CD34+ blood vessels located in the mucosa during the late stages of infection, and further disseminated in the bloodstream. These results confirmed the exposure of Shigella to plasma components during its virulence cycle. We demonstrated that all the tested Shigella strains survived plasma exposure in vitro, and we showed that Serine Protease Autotransporters of Enterobacteriaceae (SPATEs) contribute to Shigella dissemination within the colonic mucosa and in the bloodstream. We have confirmed that SPATEs are expressed and secreted in poorly oxygenated environments encountered by Shigella during late infection stages. We further demonstrated that SPATEs promoted Shigella survival in plasma, by cleaving complement component 3 (C3), thereby impairing the 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.