Pathogenic enterobacteria face various oxygen (O2) levels during intestinal colonization from the O2-deprived lumen to oxygenated tissues. Using Shigella flexneri as a model, we have previously demonstrated that epithelium invasion is promoted by O2 in a type III secretion system-dependent manner. 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 O2 is actively depleted by S. flexneri aerobic respiration—and not host neutrophils—during infection, leading to the formation of hypoxic foci of infection. This process is promoted by type III secretion system inactivation in infected tissues, favouring colonizers over explorers. We identify the molecular mechanisms supporting infectious hypoxia induction, and demonstrate here how enteropathogens optimize their colonization capacity in relation to their ability to manipulate tissue oxygenation during infection.
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The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.
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We acknowledge France-BioImaging infrastructure, supported by the French National Research Agency (ANR-10-INBS-04, Imagopole; to J.-Y.T.), ANR JCJC 2017-17-CE15-0012 (to B.S.M.) and the European Research Council (ERC grant 2009-AdG HOMEOPATH; to P.J.S.). E.T.A. was a Pasteur Foundation and Pasteur-Roux fellow.
The authors declare no competing interests.
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Tinevez, JY., Arena, E.T., Anderson, M. et al. Shigella-mediated oxygen depletion is essential for intestinal mucosa colonization. Nat Microbiol 4, 2001–2009 (2019). https://doi.org/10.1038/s41564-019-0525-3
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