Molecular Mechanisms of Helicobacter Pylori Virulence Factors for Regulating Inflammation Responses in Epithelial Cells and Macrophages

Project: A - Government Institutionb - National Science and Technology Council

Project Details


Persistent infection of H. pylori in the gastric mucosa results in release of interleukine (IL)-8, which attracts neutrophile infiltration and causes chronic gastritis. It has also been demonstrated that H. pylori could stimulate iNOS (inducible nitric oxide synthase) expression and NO (nitric oxide) production in mouse macrophages. However, H. pylori can even survive in the macrophages with massive induction of iNOS. These evidences suggested that H. pylori has a delicate mechanism to manipulate the host immune responses either to activate it or to evade killing. Nevertheless, the interactions between H. pylori and macrophages, as well as how this bacterium inhibits innate immunity in such regulations have not been extensively studied. In the first year of the proposal, a mouse macrophage infection model system will be established to demonstrate that H. pylori could inhibit lipopolysaccharide (LPS)-induced macrophage NO production and iNOS expression. The molecular mechanisms involved in mitogen-activated protein (MAP) kinase pathways, translocation of active nuclear factors will also be investigated. Upon infection, the Helicobacter pylori CagA virulence protein is injected into epithelial cells via the type IV secretion system, which is dependent on cholesterol. In the second year of this project, we will investigate whether CagA induction of IL-8 promoter depends on the presence of cholesterol, as well as AP-1 and NF-κB binding sites. In addition, the study will determine whether the CagA EPIYA (Glu-Pro-Ile-Tyr-Ala) repeat region is crucial for CagA-induced IL-8 secretion, and whether this activity depends on lipid rafts. One mechanism for H. pylori to escape from immune surveillance is assimilating and modifying cholesterol, an important cellular component of lipid raft. Following the first two years’proposals, the study will elucidate the role of cholesterol in charge of H. pylori suppressing LPS-induced NO production. It will also be explained that H. pylori evade macrophage phagocytosis or induction of autophagosome formation by disrupting bacterial antigen presentation which process in lysosome through the lipid raft signaling pathway. Studies from this proposal will provide insightful understanding of H. pylori regulating innate immune responses and bacterial pathogenesis in host stomachs.
Effective start/end date8/1/117/31/12


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