|Molecular Microbial Pathogenesis|
|HEAD||Prof. SANSONETTI Philippe / email@example.com|
|MEMBERS||Dr ARBIBE Laurence / BERGOUNIOUX Jean / Dr ENNINGA Jost / JAUMOUILLÉ Valentin
KONRADT Christoph / Dr KUFER Thomas / Dr MARTY Allison / MOUNIER Joëlle
Dr PARSOT Claude / Dr PAZ Irit / PEDRON Thierry / Dr PHALIPON Armelle / PENNO Christoph
Dr ROHDE John / Dr ROMERO Stéphane / Dr SCHNUPF Pamela / Dr SELLGE Gernot
Dr SPERANDIO Brice / Dr TOURNEBIZE Régis / Dr TRAN VAN NHIEU Guy
We apply a transdisciplinary approach to decipher the mechanisms of rupture, invasion and inflammatory destruction of mucosal barriers by pathogens, and host defenses.
paragraphShigella , the agent of bacillary dysentery, invade epithelial cells and cause inflammation of the human colonic mucosa. We have identified the major virulence genes, their regulatory mechanisms, the mode of secretion and functions of encoded effectors. We develop imaging techniques to monitor infection in cells and tissues.
A « first wave » of effector moleculesparagraph, (i.e. Ipa proteins) causes characteristic phenotypes: bacterial macropinocytosis, escape into the cytoplasm and apoptotic killing of macrophages. IcsA causes actin dependent intra/intercellular spread. Cross-talks are amplified by paracrine signals (i.e. ATP) released through connexin-based channels. Observation that Shigella invasion activates NF-κB in epithelial cells allowed us to identify Nod proteins as sensors of muropeptides released by intracellular bacteria, illustrating the « teaching potential » of pathogens regarding basic physiological processes.
Shigella also strongly regulate the generic innate response they elicit.
A « second wave » of effector moleculesparagraph, Osps and IpaHs, accounts for this regulation. OspG is a kinase that binds and inhibits functions of the ubiquitinated ubiquitine-transfer enzymes E2 involved in the degradation of I-κparagraphB, thereby making it an anti-inflammatory protein. OspF is a dual phosphatase translocating into the nucleus where it dephosphorylates MAPKs (Erk1/2, P38), causes dephosphorylation of Histone H3 and suppresses promoter accessibility to pro-inflammatory transcription factors like NF-κB, thereby acting as a potent regulator of neutrophils migration through the epithelium. OspF is also a potent regulator of adaptive immunity by suppressing expression of Th1 cytokines (i.e. IL-12 and IFNγ). IpaH molecules are a family of E3 ubiquitine ligases whose targets need identification. This is a new angle of analysis of the ways bacteria deceive host immunity, including epigenetic regulation of the innate response.
Development of vaccines. Clinical trials are underway for S. flexneri 2a and S. dysenteriae1 oral candidates. We also develop a new approach based upon conjugated, chemically-synthetized O-polysaccharide antigens.
Klebsiella infection. We study the cross-talks between Klebsiella pneumoniae and the tracheo-bronchial tree, and the functional genomics of closely related K. pneumoniae and Klebsiella rhinoscleromatis expressing opposite infection strategies.
|More informations on our web site|
|Publications 2006 of the unit on Pasteur's references database|
Activity Reports 2006 - Institut Pasteur
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