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Research > Medical Microbiology and Hospital Epidemiology > WG Prof. R. Haas > Research > 

Specific topics

Helicobacter pylori adherence and signal transduction for gastric epithelial cells

Mechanism of protein translocation by the H. pylori cag-T4SS

H. pylori vacuolating cytotoxin (VacA) receptor interaction, mechanism of uptake and immunomodulation

Role of Type IV secretion systems and mechanism of DNA transfer in H. pylori via natural transformation and conjugation.

H. pylori virulence mechanisms studied in the Mongolian gerbil animal model

Helicobacter pylori adherence and signal transduction for gastric epithelial cells
Helicobacter pylori reveals a remarkably specific adherence to gastric epithelial cells in vivo. A number of adhesins are involved, including BabA, SabA OipA and AlpAB, which belong to the large group of outer membrane protein (OMPs) of H. pylori. BabA binds the Lewis b blood group antigen (Leb), whereas SabA binds sialylated glycoproteins. For OipA and AlpAB the receptor´s are unknown. We are investigating the role of adhesins and other OMPs for the initiation of gastric infection and persistence. The signal transduction events induced by bacterial adherence to gastric epithelial cells and the nature of the receptors are analysed. We use in vitro and in vivo adherence models, such as gastric epithelial cell lines, human gastric tissue sections and the Mongolian gerbil (Meriones unguiculatus) model. Our aim is to identify bacterial components involved in adhesion signalling pathways to gastric epithelial host cells.

Mechanism of protein translocation by the H. pylori cag-T4SS
The H. pylori cag-T4SS is a complex molecular machine consisting of a transmembrane transport channel and a surface pilus dedicated to specifically translocate the bacterial protein CagA into gastric host cells. Translocation of CagA protein requires beta-1 integrin as a receptor on the surface of host cells. In this project we are currently unravelling the unique and complex interaction of components of the H. pylori cag-T4SS with the beta-1 integrin receptor to understand the molecular mechanism of how protein translocation works. We therefore use specific H. pylori mutant strains, protein-protein interaction screens, other biochemical methods and novel microscopic techniques.

H. pylori vacuolating cytotoxin (VacA) receptor interaction, mechanism of uptake and immunomodulation

VacA is a protein toxin secreted by H. pylori, which induces cellular vacuolation in epithelial cells. The autotransporter protein of 140 kDa is processed to a 90 kDa mature protein, which forms hexameric structures and pores into membranes. We identified an activity of VacA involved in inhibition of T lymphocyte proliferation and cytokine secretion, especially interleukin-2 (IL-2). VacA specifically inhibits the Ca2+-calmodulin-dependent phosphatase calcineurin and induces cell cycle arrest. Thus, VacA mimics the activity of the immunosuppressive drugs, such as cyclosporin A or FK506. We recently identified the beta-2 integrin subunit CD18 as the receptor for vacA on T lymphocytes. Our current project deals with basic questions about (i) VacA receptor binding and uptake into T cells, (ii) the mechanism of entry of endocytosed VacA into the cytosol and (iii) the molecular mechanism of calcineurin inhibition.

Type IV secretion systems and mechanism of DNA transfer in H. pylori via natural transformation and conjugation
H. pylori is one of the genetically most diverse bacterial species known. Clinical isolates of H. pylori are naturally competent to take up chromosomal DNA of the same species for genetic recombination, which is considered to be the basis for their high genetic variability. In addition, plasmids of H. pylori have been identified, which carry putative mobilization regions, suggesting that such plasmids might be exchanged between H. pylori species via bacterial conjugation. In this project, we intend to analyse the mechanisms underlying both, natural transformation and possibly plasmid conjugation. Transformation competence is mediated by the comB T4SS of H. pylori, but the T4SS that mediates plasmid conjugation is not known so far.

H. pylori virulence mechanisms studied in the Mongolian gerbil animal model (Meriones unguiculatus)
The H. pylori mouse model is not suitable to study major virulence factors of H. pylori, such as the cag-T4SS or VacA. The cag-T4SS is unstable in H. pylori strains infecting mice, whereas murine T cells do not respond to VacA. We therefore established the Mongolian gerbil model, which allows a stable infection with adapted type I H. pylori strains inducing a strong inflammation and gastric disease (gastric ulcers, atrophic gastritis, dysplasia). This model is currently used to unravel basic questions of H. pylori mediated disease induction under in vivo conditions. They range from the identification of bacterial colonization factors, via the mechanism of horizontal DNA transfer and genetic variation, to the mechanism of H. pylori mediated gastric cancer induction.