Research / Integrative Biology of Emerging Infectious Diseases (IBEID) / Principal investigators
Molecular Microbial Pathogenesis Unit
Institut Pasteur 25-28 rue du docteur Roux, 75015 Paris
Research area of the Unit
Our work addresses the pathogenesis of bacterial enteric infections and the mechanisms of gut homeostasis in presence of the microbiota.
Following our discovery of a virulence plasmid in Shigella encoding cell invasion, we characterized its mechanisms of rupture, invasion and inflammatory destruction of the intestinal epithelium, identifying key factors ; type III secretion system (TTSS), actin-dependant entry into epithelial cells and cytoplasmic escape, actin-dependant cell to cell spread, caspase-1 dependant proinflammatory apoptosis of macrophages. We also provided an integrated view of infection in vivo, showing how the host senses the bacterial danger and how the pathogen uses and subverts the innate immune response to disrupt the epithelial barrier and survive immune defenses. We also developed novel vaccine strategies against shigellosis.
Recently, we have unraveled novel concepts: Intracellular sensing of bacteria, leading to our discovery of Nod molecules as cytosolic sensors, and muropeptides as proinflammatory agonists. Existence of a library of TTSS effectors regulating host responses by postranslational modifications of molecules in the NF-B and MAPKinase pathways, engaging genetic and epigenetic repression of innate immunity genes. Subversion of cellular mechanisms of secretion. Manipulation of connexin-based hemichannel functions of ATP secretion repressing danger signals. Blocking of T-cell migration by hydrolysis of PIP2.
We have also started to decipher how symbionts achieve homeostasis of the intestinal epithelium, particularly in the intestinal crypt, a strategic area in which stem cells maintain epithelial restitution.
Contribution to the programme
Our contribution to the program is threefolds:
1 - We bring our expertise in analyzing the pathogenesis of infection using a multidisciplinary approach encompassing molecular genetics, genomics, cell biology, biochemistry, immunology and experimental medicine. In case of emergence of a novel bacterial pathogen, we should be able to support an integrated program aimed at deciphering its pathogenic process, based on the development of in vitro and in vivo approaches.
2 – We bring our expertise in vaccine development that goes from identification of protective antigens, to strategic choice of the type of vaccine to be developed and its optimal mode of administration. We also bring our experience in clinical trials and network of collaborations abroad.
3 – We bring our recently developed expertise in studying the mechanisms of epithelial homeostasis in the presence of the microbiota, particularly in the context of epithelial restitution. This is essential to address emerging inflammatory diseases that increasingly occur in response to altered homeostatic mechanisms of response to the microbiota.
References over the past 5 years
1. ARBIBEL., KIMD.W., BATSCHEE., PEDRONT., MATEESCUB., MUCHARDTC., PARSOTC., 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.
2. 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.
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.
4. LAUNAY O, SADORGE C, JOLLY N, POIRIER B, BECHET S, VAN DER VLIET D, SEFFER V, FENNER N, DOWLING K, GIEMZA R, JOHNSON J, NDIAYE A, VRAY M, SANSONETTI P, MORAND P, POYART C, LEWIS D, GOUGEON ML.
Safety and immunogenicity of SC599, an oral live attenuated Shigella dysenteriae type-1 vaccine in healthy volunteers: results of a Phase 2, randomized, double-blind placebo-controlled trial.
Vaccine. 2009 Feb 18;27(8):1184-91.
5. MARTEYN B, WEST NP, BROWNING DF, COLE JA, SHAW JG, PALM F, MOUNIER J, PREVOST MC, SANSONETTI P, TANG CM.
Modulation of Shigella virulence in response to available oxygen in vivo.
Nature. 2010 May 20;465(7296):355-8.
6. KONRADT C, FRIGIMELICA E, NOTHELFER K, PUHAR A, SALGADO-PABON W, DI BARTOLO V, SCOTT-ALGARA D, RODRIGUES CD, SANSONETTI PJ, PHALIPON A.
The Shigella flexneri type three secretion system effector IpgD inhibits T cell migration by manipulating host phosphoinositide metabolism.
Cell Host Microbe. 2011 Apr 21;9(4):263-72.
7. PEDRON T, MULET C, DAUGA C, FRANGEUL L, CHERVAUX C, GROMPONE G, SANSONETTI PJ.
MBio. 2012 May 22;3(3). pii: e00116-12.