HelicobacterPathogenesis  


  HEADDr. DE REUSE Hilde / hilde.de-reuse@pasteur.fr
  MEMBERSPermanent: Dr TOUATI Eliette Temporary: Dr BUSSIERE Françoise / Dr LEDUC Damien / Dr. MULLER Cécile / Dr SCHAUER Kristine / Dr THIBONNIER Marie Research engineer and technicians: AUBERT Sylvie / MICHEL Valérie


  Annual Report

Helicobacter pylori is a bacterial pathogen colonizing the stomach of about half of the world's human population. Infection by H. pylori is chronic and can evolve from gastritis to severe pathologies such as peptic ulcers and gastric cancer accounting for more than half a million deaths per year worldwide. H. pylori is till now the only bacteria to be recognized as a type 1 carcinogenic agent. In addition to this public health issue, H. pylori is of particular interest because it is the only microorganism to persistently colonize the human gastric mucosa, its unique niche, which makes it an excellent model organism to address fundamental questions related to its adaptation to such an hostile acidic environment.

Our research focuses on the pathogenesis of this gastric pathogen by studying both the bacterial virulence factors and the host response. First, we aim at identifying and characterizing the H. pylori factors and mechanisms that make this bacteria a successful and persistent pathogen in an hostile ecological niche. Second, we investigate the mechanisms involved in the induction of genotoxic eventsby H. pyloriinfection and their role in the development of malignant lesions. Approaches comprise genetics, genomics, proteomics, RNA analysis, cell biology and animal models.

Recent studies

Nickel trafficking and metabolism in H. pyloriNickel is the co-factor for two essential metallo-enzymes of H. pylori, hydrogenase and the very abundant urease that is required for acid resistance. We have identified a novel TonB-dependent mechanism for energized nickel uptake through the outer membrane. This finding set the basis for a bioinformatic analysis (with D. R. Rodionov, Burnham Institute) that revealed a previously underestimated number and variety of substrates dependent on TonB for energized transport in gram negative bacteria.

Interactome of H. pyloriWe adapted the tandem affinity purification (TAP) technology for the study of protein-protein complexes in H. pylori. The urease complex provides new insight into coupling between ammonium production and assimilation. In addition, an in vivo interaction between the nickel maturation systems for urease and hydrogenase was evidenced. This technology is currently applied to the study of several complexes related to virulence and adaptation factors of H. pylori.

Trans-translation, an essential quality control mechanism in H. pyloriTrans-translation is a quality control mechanism that requires two partners, SsrA a small stable RNA and the SmpB protein. It rescues ribosomes that are sequestered on defective mRNAs and adds a tag to the truncated protein to direct it to degradation pathways. We found that in H. pylori,trans-translation dependent ribosome rescue is an essential function while protein tagging is required for both stress resistance and competence.

Genotoxicity associated to the H. pylori infectionUsing the transgenic big blue mouse model, that allows detection of mutations in any organ, we provided the first direct evidence that long term chronic infection by H. pyloriinduces a mutagenic effect at the gastric mucosa level mainly due to gastric inflammation. We recently showed that H. pylori impairs central DNA repair mechanisms including the mismatch repair system, leading to the accumulation of genetic instability, thus contributing to early events in the gastric neoplastic process.

In order to identify genes potentially involved in the development of malignant lesions, we investigated the global gene expressionprofile in response to a chronic infection by H. pylori in the mouse model. Our data revealed an IFNγ transcripts signature with an up-regulation of interleukin IL-23, this response was also observed using gastric biopsies of H. pylori infected-patients.

Keywords: Helicobacter – gastritis – tandem affinity purification - gastric carcinoma – ulcer – lymphoma – MALT - signalization – resistance to acidity – inflammation –comparative genomics – proteomics – regulation - urease - nickel – mouse model -genotoxicity

Pph.jpg

Large lymphocyte follicles visualized in the mouse gastric mucosa infected by H. pylori strain SS1 during 18 months (with the help of M. Huerre, Unité de Recherche et d'Expertise Histotechnologie et Pathologie ).



  Publications

Thibonnier, M., Thiberge, J-M and De Reuse, H. (2008) Trans-Translation in Helicobacter pylori: Essentiality of Ribosome Rescue and Requirement of Protein Tagging for Stress Resistance and Competence. PlosOne 3(11): e3810PMID: 19043582

Stingl, K., Schauer, K., Ecobichon, C., Labigne, A., Lenormand, P., Rousselle J-C., Namane, A. and De Reuse H. (2008)In vivo interactome of Helicobacter pylori urease revealed by tandem affinity purificationMolecular and Cellular Proteomics 7:2429-41.PMID: 18682379

Vivas, J. R., Régnault, B. Michel, V., Bussière, F. I., Avé, P., Huerre, M., Labigne, A., D'Elios, M. M. and Touati, E. (2008)Interferon g-signature transcripts profiling and IL-23 upregulation in response to Helicobacter pyloriinfectionInternational Journal of Immunopathology and Pharmacology 21: 515-526.PMID: 18831919

Schauer, K., Rodionov, D.A. and De Reuse, H (2008) "New substrates for TonB-dependent transport: Do we only see the tip of the iceberg ? "Trends In Biochemical Sciences 33: 330-338

Schauer, K., Gouget, B., Carrière, M., Labigne, A. and De Reuse H. (2007)Novel nickel transport mechanism across the bacterial outer membrane energized by the TonB/ExbB/ExbD machinery Molecular Microbiology 63:1054-1068.PMID: 17238922





Activity Reports 2009 - Institut Pasteur
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