Molecular Microbial Pathogenesis - INSERM U786, Collège de France  


  HEADProf. Philippe SANSONETTI / psanson@pasteur.fr
  MEMBERSJACQUEMIN Colette, cjacmin@pasteur.fr /PARSOT Claude, IP, Chef de Laboratoire, cparsot@pasteur.fr/ PHALIPON Armelle, IP, Chef de Laboratoire, phalipon@pasteur.fr / TRAN VAN NHIEU Guy, INSERM, DR2, gtranvan@pasteur.fr / TOURNEBIZE Régis, INSERM, CR2, tournebi@pasteur.fr /ARBIBE Laurence, INSERM CR1, arbibe@pasteur.fr
PAZ Irit, Post-doc (left in June 2007) / ROHDE John, Post-doc (left in April 2007) / SELLGE Gernot, Post-doc / ENNINGA Jost, Post-doc / KUFER Thomas, Post-doc (left in October 2007) / SPERANDIO Brice, Post-doc / SCHNUPF Pamela, Post-doc / ROMERO Stéphane, Post-doc / PENNO Christophe, PhD Student (left in April 2007) / JAUMOUILLÉ Valentin, PhD Student / BERGOUNIOUX Jean, PhD Student (left in November 2007) / KONRADT Christoph, PhD Student / BRINGER Marie-Agnès, Post-doc / HAROUZ Habiba, PhD Student / MARTY Allison, Post-doc
PEDRON Thierry, IP Engineer, tpedron@pasteur.fr / MOUNIER Joëlle, IP Engineer, jmounier@pasteur.fr / TANGUY Myriam, IP Technician, mtanguy@pasteur.fr / AGERON Elisabeth, INSERM Technician, eageron@pasteur.fr / MULET Céline, IP Technician, cmulet@pasteur.fr


  Annual Report

We apply a transdisciplinary approach to decipher the mechanisms of rupture, invasion and inflammatory destruction of mucosal barriers by pathogens, and host defenses.

Shigella, 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 molecules, (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 molecules, 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-κB, thereby making it an anti-inflammatory protein. OspF translocates 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 new 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. Most recent results indicate that these effectors suppress expression of epithelial anti-microbial peptides.

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-synthetised 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.

Keywords: Shigella, inflammation, invasion, immunity, Klebsiella

Pmm.jpg

Polar secretion of invasion protein IpaC during HeLa cells infection by Shigella. Green: bacteria, red: IpaC, blue: actin.



  Publications

WEST NP*, SANSONETTI P*, MOUNIER J, EXLEY RM, PARSOT C, GUADAGNINI S, PREVOST MC, PROCHNICKA-CHALUFOUR A, DELEPIERRE M, TANGUY M, TANG CM, 2005.Optimization of virulence functions through glucosylation of ShigellaLPS. Science, 307: 1313-1317 (*co-first authors)

ENNINGA, J., MOUNIER, J., SANSONETTI, P.J., TRAN VAN NHIEU, G. 2005. Studying the ecretion of Type III effectors into host cells in real time. Nature Methods, 2(12) : 959-965.

KIM DW, LENZEN G, PAGE AL, LEGRAIN P, SANSONETTI PJ, PARSOT C, 2005. The Shigella flexneri effector OspG interferes with innate immune responses by targeting ubiquitin-conjugating enzymes. Proc Natl Acad Sci U S A. 102(39):14046-51.

PHALIPON A, COSTACHEL C, GRANDJEAN C, THUIZAT A, GUERREIRO C, TANGUY M, NATO F, VULLIEZ-LE NORMAND B, BELOT F, WRIGHT K, MARCEL-PEYRE V, SANSONETTI P, MULARD, LA, 2006 Characterization of functional oligosaccharide mimics of the Shigella flexneri serotype 2a O-antigen: implications for the development of a chemically defined glycoconjugate vaccine. J. IMMUNOL., 176 : 1686-94.

ARBIBEL., KIM D.W., BATSCHE E., PEDRON T., MATEESCU B., MUCHARDT C., PARSOT C., SANSONETTI, P.J., 2007. An injected bacterial effector targets chromatin access for nuclear factor kappa B to alter transcription of host immune genes. Nature Immunology, 8(1):47-56.



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Activity Reports 2007 - Institut Pasteur
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