Involvement of Glycosphingolipids and Toll-Like Receptors in Response to Helicobacter Pylori Infection in Gastric Epithelial Cells

Helicobacter pylori infection is thought to be involved in several gastrointestinal diseases. Several H. pylori virulence factors are reportedly associated with lipid rafts of gastric epithelial cells. The role of Toll-like receptors (TLRs) in signaling H. pylori infection has been investigated extensively in host cells. However, the receptor molecules for H. pylori infection of gastric epithelial cells, which are present in lipid rafts and induce inflammatory responses, have not been well characterized. In this proposal of the first year, we will investigate whether infection of cells with H. pylori induced acid sphingomyelinase (ASM) and ceramide secretion, and TLR4/MD-2 expression, and thereby contribute to inflammation in gastric epithelial cells. In the second year of this project, we will analyze whether the level of cellular ceramide was elevated and it was translocated into lipid rafts after H. pylori infection, leading to interleukin-8 (IL-8) production. In the third year, the role of H. pylori-induced ceramide/TLR4 signaling is dependent on cholesterol-rich microdomains will be validated in an in vivo mouse model system. Studies from this proposal will provide important insights into H. pylori regulating innate immune responses and bacterial pathogenesis in host stomachs.