探討幽門螺旋菌侵入胃上皮細胞及其毒力因子與脂質筏之相關

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Title:	探討幽門螺旋菌侵入胃上皮細胞及其毒力因子與脂質筏之相關
Other Titles:	Investigation of the Roles of Cellular Lipid Rafts and Bacterial Virulence Factors in Helicobacter pylori Internalization into Gastric Epithelial Cells
Authors:	賴志河(Chih-Ho Lai);王雯靜(Wen-Ching Wang)
Contributors:	醫學院醫學系學士班微生物學科
Keywords:	幽門螺旋菌;毒力因子;脂質筏
Date:	2007-07-31
Issue Date:	2009-09-01 16:23:25 (UTC+8)
Abstract:	脂質筏(lipid rafts) 是位於細胞膜上的微小區域，主要是由磷脂質、鞘脂質與膽固醇所組成。這種微小的區域不僅是細胞膜上動力學的結構，而且可提供更多的訊息傳遞來活化細胞。近年來的研究更是發現有許多病原體很可能都是藉由與脂質筏的相互作用，使其形成一個捷徑而讓微生物能感染細胞進而侵入宿主的細胞內。我們先期的研究發現，幽門螺旋菌導致宿主致病的原因可能與細菌的一些毒力因子有很高的相關性。然而對於細菌是如何侵入細胞內，尤其是細胞內發生何種訊息改變仍然有許多未知之處。本計畫主要目的是探討幽門螺旋菌感染細胞時侵入細胞內的詳細過程，而一些參與細菌感染細胞的毒力因子都將一一探討。更進一步，我們將深入研究脂質筏內的分子，並設法找出哪些特定分子會直接與細菌直接交互作用。主要研究的目標包含下列︰(一) 探討何種細菌表面的毒力因子是提供幽門螺旋菌侵入細胞之要角、(二) 探討caveolae 與caveolin-1 在幽門螺旋菌侵入細胞時所扮演的角色、(三) 利用系統性蛋白質體分析的方法(proteomic approach) 來分析CagA–陽性與CagA–陰性的幽門螺旋菌與宿主細胞脂質筏分子之交互作用的差異。這些基礎研究不但可以使我們更清楚瞭解幽門螺旋菌與宿主細胞之相互作用，而且將來在臨床上，更可以促進發展新的策略來防止細菌的持續性感染。 Infection of Helicobacter pylori cagA-positive strains is associated with gastritis, ulcerations and gastric cancer. CagA is translocated into infected epithelial cells by type IV secretion system and can be tyrosine phosphorylated, inducing signal transduction and motogenic responses in epithelial cells. Cellular cholesterol, a vital component of membrane, contributes to membrane dynamics and functions and is important in VacA intoxication and phagocyte evasion during H. pylori infection. In this investigation, we showed that cholesterol extraction by methyl-beta-cyclodextrin reduced the level of CagA translocation and phosphorylation. Confocal microscope visualization revealed that a significant portion of translocated CagA was colocalized with rafts marker GM1 and c-Src during infection. Moreover, CagA and VacA were co-fractionated with detergent-resistant membranes (DRMs), suggesting that distribution of CagA and VacA was associated with rafts in infected cells. Upon cholesterol depletion, their distribution shifted to non-DRMs. Accordingly, CagA-induced hummingbird phenotype and IL-8 induction was blocked by cholesterol depletion. We showed that raft-disrupting agents did not influence bacterial adherence but did significantly reduce internalization activity in AGS cells. These results together suggest that delivery of CagA into epithelial cells by the bacterial type IV secretion system is mediated via a cholesterol-dependent manner.
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