Mechanism of Helicobacter pylori DNA exchange and microcin delivery

幽门螺杆菌感染与许多胃十二指肠疾病有关，包括慢性胃炎、消化性溃疡、腺癌和粘膜相关淋巴组织淋巴瘤。大约50%的临床幽门螺杆菌分离株携带大小和基因含量高度可变的质粒，然而，这些质粒的生物学功能在很大程度上是未知的。幽门螺杆菌质粒的一个亚群携带DNA动员（mob）基因，一个假定的新型毒素-抗毒素（TA）系统，以及一个编码假定的细菌微霉素的操纵子。在本项目中，我们有兴趣了解(1)幽门螺杆菌质粒pHel4的DNA转移和质粒维持功能；(2)推定的幽门螺杆菌质粒编码微霉素的结构和功能。我们希望鉴定出一种新的质粒转移系统，因为迄今为止已知的幽门螺杆菌供体菌株中的IV型分泌系统（T4SS），如cage - pai和comB系统，不参与质粒转移。本文将研究一个用于合成修饰七肽微霉素的7个氨基酸编码基因及其遗传调控。本文将分析微霉素的自我耐受和分泌机制、微霉素的靶生物及其在靶细胞中的作用方式。DNA转移和微霉素的产生都将通过适当的动物模型在体内进行评估。

Helicobacter pylori infection is associated with a number of gastroduodenal diseases, including chronic gastritis, peptic ulcers, adenocarcinoma and mucosa-associated-lymphoid tissue lymphoma. About 50% of clinical H. pylori isolates carry plasmids of highly variable size and gene content, however, the biological function of these plasmids is largely unknown. A subgroup of cryptic H. pylori plasmids carry DNA mobilization (mob) genes, a putative novel toxin-antitoxin (TA) system as well as an operon encoding a putative bacterial microcin. In this project we are interested to understand (1) the DNA transfer and plasmid maintenance functions in H. pylori plasmid pHel4 and (2) the structure and function of a putative plasmid-encoded microcin of H. pylori. We expect to identify a novel plasmid transfer system, since so far known type IV secretion systems (T4SS) in the H. pylori donor strain, such as the cag-PAI and the comB system, are not involved in plasmid transfer. A putative seven amino acid-encoding gene for the synthesis of a modified heptapeptide microcin and its genetic regulation will be studied. The mechanism of microcin self-tolerance and secretion, the microcin target organisms and its mode of action in target cells will be analyzed. Both, DNA transfer and microcin production will be assessed in vivo using appropriate animal models.