Modulation of Shigella virulence in response to available oxygen in vivo

Abstract

Bacteria co-ordinate expression of virulence determinants in response to localised microenvironments in their hosts. Here we show that Shigella flexneri, which causes dysentery, encounters varying oxygen concentrations in the gastrointestinal (GI) tract, which govern activity of its type three secretion system (T3SS); the T3SS is essential for cell invasion and virulence 1 . In anaerobic environments (e.g. the GI tract lumen), Shigella expresses extended T3SS needles while reducing Ipa (Invasion plasmid antigen) effector secretion. This is mediated by FNR, a regulator of anaerobic metabolism that represses transcription of spa32 and spa33, virulence genes that the switch in secretion through the T3SS. We demonstrate there is a zone of relative oxygenation adjacent to the GI tract mucosa, caused by diffusing from the capillary network at the tips of villi. This would reverse the anaerobic block of Ipa secretion, allowing T3SS activation at its precise site of action, enhancing invasion and virulence.Shigella virulence depends on its ability to enter epithelial cells by delivering Ipa effectors via its T3SS into the host cell cytoplasm 1 . Secretion through T3SSs is highly regulated.Initially, T3SS needle components are secreted until it reaches a pre-defined length 23 . In inducing conditions, a switch then occurs allowing Ipa secretion through needles, mediating bacterial entry 4 .

Functional genomics of Lactobacillus casei establishment in the gut

“…We could not carry out long-term colonization experiments in the mouse intestine because the level of colonization following intragastric administration was insufficient to allow the reliable tracking of each individual mutant composing the injected pool. As an alternative, we validated the rabbit ligated ileal loop model that has been shown to be well adapted to STM screening in Shigella (24)(25)(26). Because colonization of ligated loops cannot be carried out for more than 16 h, this assay explores the initial survival of mutants to gut luminal conditions and their early steps of colonization, hence the term "establishment.…”

“…Because most bacterial genes are organized in operons [1.5 genes per transcription unit predicted for L. casei, according to genome analysis using the Biocyc website (23)], transposon integration can cause a polar effect; thus the location of each gene of interest in a given operon is specified. The rabbit ligated ileal loop model allowed the screening of a large number of Shigella mutants in competitive pools in the gut (24)(25)(26), and it explores the ileal conditions in which L. casei has been shown to persist in an active physiological state (27).…”

Évolution adaptative des bactéries

“…patients de mucoviscidose, et qui rappelle la relation décrite entre sensibilité à l'oxygène in vivo et virulence de Shigella [7]. Cette étude d'évolution bactérienne in vivo a donc permis de préciser les mécanismes de pathogenèse de l'infection dans la mucoviscidose, et elle pourrait suggérer de nouvelles cibles thérapeutiques.…”

The Inside Story of Shigella Invasion of Intestinal Epithelial Cells

“…FNR was shown to regulate the synthesis of the T3SA genes, resulting in secretion apparatus with elongated needles, presumably primed but repressed for injection of effectors. At the close vicinity of colonic intestinal epithelial cells, the microaerophilic environment leads to FNR repression and activation of secretion to promote bacterial invasion (Marteyn et al 2010). In the intracellular environment, carbon source and iron limitation may also regulate the expression of VirF/VirB-dependent genes.…”