ABSTRACT

Helicobacter pylori infection is associated with several gastrointestinal diseases, including gastritis, peptic ulcers, and gastric cancer. Infection of cells with H. pylori is dependent on lipid rafts, which are cholesterol-rich microdomains located in the cell membrane. H. pylori cholesterol-α-glucosyltransferase (CGT) catalyzes the conversion of membrane cholesterol to cholesteryl glucosides, which can be incorporated into the bacterial cell wall, facilitating evasion from immune defense and colonization in the host. However, the detailed mechanisms underlying this process remain to be explored. In this study, we discovered for the first time that H. pylori CGT could promote adherence to gastric epithelial cells in a cholesterol-dependent manner. Externalization of cell membrane phosphatidylserine (PS) is crucial for enhancement of binding of H. pylori to cells by CGT and for cytotoxin-associated gene A (CagA)-induced pathogenesis. Furthermore, exogenous cholesterol interferes with the actions of H. pylori CGT to catalyze cellular cholesterol, which impedes bacterial binding to cells and attenuates subsequent inflammation, indicating that the initial attachment of H. pylori to cells is closely dependent on host cholesterol. These results provide evidence that CGT contributes to H. pylori infectivity and it may serve as a key target for the treatment of H. pylori-associated diseases.

摘要

幽门螺杆菌感染与多种胃肠道疾病有关，包括胃炎、消化性溃疡和胃癌。幽门螺杆菌感染细胞依赖于脂筏，脂筏是位于细胞膜中的富含胆固醇的微区。H. pylori胆固醇-α-葡糖基转移酶 (CGT) 催化膜胆固醇转化为胆固醇糖苷，胆固醇糖苷可掺入细菌细胞壁，促进逃避免疫防御和在宿主中定殖。然而，这一过程背后的详细机制仍有待探索。在这项研究中，我们首次发现了H. pyloriCGT可以以胆固醇依赖的方式促进对胃上皮细胞的粘附。细胞膜磷脂酰丝氨酸 (PS) 的外化对于通过 CGT 增强幽门螺杆菌与细胞的结合以及细胞毒素相关基因 A (CagA) 诱导的发病机制至关重要。此外，外源性胆固醇会干扰H. pylori CGT 催化细胞胆固醇的作用，从而阻碍细菌与细胞的结合并减轻随后的炎症，表明H. pylori与细胞的初始附着密切依赖于宿主胆固醇。这些结果提供了 CGT 有助于H. pylori感染性的证据，它可能作为H. pylori治疗的关键靶点-相关疾病。