Molecular Microbial Pathogenesis - NSERM U786 Collège de France  


  HEADPhilippe 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
SELLGE Gernot, Post-doc / SPERANDIO Brice, Post-doc / SCHNUPF Pamela, Post-doc / ROMERO Stéphane, Post-doc / PRUNIER Anne-Laure, Post-doc / MATSUKI Takahiro, Post-doc / PUHAR Andrea, Post-doc / SALGADO-PABON Wilmara, Post-doc / TARONT Solenne, Post-doc / BRINGER Marie-Agnès, Post-doc (left October 2008) / MARTY Allison, Post-doc (left December 2008) / JAUMOUILLÉ Valentin, PhD Student / HAROUZ Habiba, PhD Student / KONRADT Christoph, PhD Student / ELISEE Ruben, PhD Student / ALMEIDA Ana Margarida, PhD Student / BONGRAND Clotilde, PhD Student
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 / DONNADIEU Françoise, IP Technician, fdonna@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, invades 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 polarly secreted 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. Very early steps of bacterial capture at cell surface through nanopodial structures have been unravelled and analyzed (Figure). Observation that Shigella invasion activates NF-κB in epithelial cells allowed us to identify Nod proteins as sensors of muropeptides released by intracellular bacteria. We are now showing that Shigella also strongly regulate the elicited innate response by expressing and secreting a « second wave » of effector molecules, Osp and IpaH. 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 MAPKinases (Erk1/2, P38), causes dephosphorylation of Histone H3 and suppresses accessibility to selected promoters like IL-8 to pro-inflammatory transcription factors, 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 form 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. Recent results demonstrate that these effectors suppress the expression of epithelial anti-microbial peptides and the trafficking of dendritic cells.

We have started a new theme aimed at understanding how commensal bacteria maintain the homeostasis of the epithelial crypt-villous axis of the gut and how it is disrupted by pathogens like Shigella.

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.

Klebsiellainfection : we study the cross-talks between Klebsiella pneumoniae with the tracheo-bronchial tree, and the functional genomics of closely-related K. pneumoniae and Klebsiella rhinoscleromatis expressing opposite infection strategies respectively acute, hyperinflammatory and chronic granulomatous.

Keywords: Shigella, inflammation, invasion, immunity, Klebsiella

Pmm.jpg

Fig. LEGEND: Shigella interaction with filopodial extensions during the early steps of bacterial invasion

HeLa cells challenged with wild-type Shigella . Left : scanning electron microscopy. Right : Green: Src-GFP

Immunofluorescence staining of bacterial LPS (blue), F-actin (red). (Grompone et al, manuscript in preparation)



  Publications

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.

ROHDE, J. R., BREITKREUTZ, A. CHENAL, A., SANSONETTI, P. J., PARSOT, C. 2007

Type III secretion effectors of the IpaH family are E3 ubiquitin ligases.

Cell Host Microbe, 1: 77-83.


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.


SPERANDIO B, REGNAULT B, GUO J, ZHANG Z, STANLEY SL Jr, SANSONETTI PJ, PEDRON T

Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression.

J Exp Med. 2008 May 12;205(5):1121-32.


JAUMOUILLE V, FRANCETIC O, SANSONETTI PJ, TRAN VAN NHIEU G.

Cytoplasmic targeting of IpaC to the bacterial pole directs polar type III secretion in Shigella.

EMBO J. 2008 Jan 23;27(2):447-57.



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Activity Reports 2009 - Institut Pasteur
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