Shigella-mediated oxygen depletion is essential for intestinal mucosa colonization

Pathogenic enterobacteria face various oxygen (O(2)) levels during intestinal colonization from the O(2)-deprived lumen to oxygenated tissues. Using Shigella flexneri as a model, we had previously demonstrated that epithelium invasion is promoted by O(2) in a Type III secretion system (T3SS)-dependent manner(1). However, subsequent pathogen adaptation to tissue oxygenation modulation remained unknown. Assessing single-cell distribution, together with tissue oxygenation, we demonstrate here that the colonic mucosa O(2) is actively depleted by Shigella flexneri aerobic respiration, not host neutrophils, during infection, leading to the formation of hypoxic foci of infection. This process is promoted by T3SS inactivation in infected tissues, favoring colonizers over explorers. We identify the molecular mechanisms supporting infectious hypoxia induction, and we demonstrate here how enteropathogens optimize their colonization capacity in relation to their ability to manipulate tissue oxygenation during infection.