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Rupture, Invasion and inflammatory destruction of the intestinal epithelium by Shigella: War and Peace at mucosal surface

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Rupture, invasion and inflammatory destruction of the intestinal epithelium by Shigella : War and Peace at mucosal surface. Philippe Sansonetti, Unité de Pathogénie Microbienne Moléculaire, Unité INSERM 786 , and Howard Hughes Medical Institute, Institut Pasteur, Paris, France.

Shigella, a gram-negative enteropathogenic bacteria cause the rupture, invasion and inflammatory destruction of the human rectal and colonic epithelia. It is a major cause of mortality and morbidity among pediatric populations in the most impoverished areas of the planet and an efficient vaccine is still awaited. Understanding the molecular bases of the pathogenic process of shigellosis is essntial to develop vaccine candidates against dysentery. The invasive phenotype of Shigella is encoded by a large plasmid of 220 kb encoding a Type III Secretory System (TTSS) and cognate effector molecules that are injected by this TTSS into the membrane and cytoplasm of eukaryotic cell targets in the course of the infectious process. Injected effectors can be subdivided into two major categories (i) Ipa proteins that are mainly involved in the formation of the translocating structure of the TTSS , and triggering of the massive actin cytoskeletal rearrangements that carry out the entry process via macropinocytosis. (ii) Osp and IpaH proteins whose genes are only transcribed when the TTSS is functional. Ongoing work indicates that these proteins are major regulators of the innate and adaptive immune responses of the mucosa to the invading pathogen. They act very specifically upon key steps of major signalling pathways such as NF-B and MAPK , through specific enzymatic activitie. OspG, for example, is a kinase that binds a subgroup of E2 ubiquitine-ligases, thereby blocking ubiquitination of I-B and activation of the pro-inflammatory genes that are under the control of this essential pathway. OspF is a dual phosphatase that reaches the cell nucleus where it dephosphorylates active Erk1/2 and P38 , thereby regulating histone phosphorylation, chromatin compaction and the transcription of a set of inportant pro-inflammatory genes including IL-8 ; this, by the way, being the first example of epigenetic modification of gene transcription by a bacterial effector. IpaH molecules correspond to a family of 10 proteins that share a common enzymatic activity of ubiquitine E3 ligase of the HECT type. It now remains to figure out how these effectors conjugate efforts to « carve » a particular profile of immune genes transcription in their target cells, in which order it is performed, and to which extent it affects bacterial colonisation and invasion capacity, as well as the profiles of innate and adaptive responses. In order to achieve this, we are developing imaging tools to follow delivery of these effectors into cells in real time, both in vitro and in vivo, as well as humanized transgenic mice able to develop shigellosis. The process of individual cell invasion is considerably amplified in epithelial cells by the capacity of Shigella that escape the endocytic membrane to move intracellularly and pass from one cell to another, following surface activation of actin nucleation by an outer membrane protein, IcsA. This highly regulated process of intercellular spread also allows bacteria to resist host defenses mechanisms. Beyond the interest of deciphering the detailed mechanisms of a disease and of the host response, it is important to emphasize that tracing Shigella in its « journey » through the gut has also unravelled mechanisms of much broader interest, such as the Nod system of intracellular sensing of bacteria through their released muropeptides. We also hope to « harness » the effectors that regulate host immune responses to help develop new targets and drugs, particularly in the field of anti-inflammatory and immunomodulatory agents.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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