幽门螺杆菌响应Th1-IFN-γ免疫动态增减cagA拷贝数作为其致病性调控的新机制

幽门螺杆菌（Hp）毒力因子CagA在胃炎、胃癌发生中起关键作用。我们已报道：Hp可携带多个cagA基因拷贝，通过同源重组增减拷贝数，显著改变Hp致病性，但Hp维持高拷贝数cagA的机制尚不明确。预实验显示：感染初期，cagA拷贝数无明显变化，高拷贝数cagA致病性显著增加；感染中后期，高拷贝数cagA减少，Hp致病性减弱，Th1-IFN-γ免疫可能是促cagA拷贝数减少的关键。据此我们推测：当Th1-IFN-γ免疫低下时，Hp可维持高拷贝数cagA而致病。本项目拟开展:通过不同cagA拷贝数Hp感染小鼠模型探讨cagA拷贝数调控Hp致病性的具体机制；利用免疫缺陷小鼠、细胞过继转移实验等明确IFN-γ的关键作用；最终由免疫抑制小鼠模型证实Th1-IFN-γ免疫低下时，Hp维持高拷贝数cagA而致病。本项目将完整阐明cagA拷贝数变化规律和致病机制，为防治Hp感染和相关胃部疾病提供科学依据。

Helicobacter pylori（Hp) transfers its virulence factor CagA into host cells, which plays a significant role in development of gastric disease such as gastritis and gastric cancer. In our previous studies, we showed that some Hp strains harbored multiple cagA gene copies, and Hp could change cagA copy number dynamically via homologous recombination, which also changed its pathogenicity significantly. However, the mechanism in which Hp kept higher number of cagA copies and being more pathogenic remains to be elucidated. In current study, we showed that higher cagA copy number induced more pathogenic phenotypes 4 weeks post infection in mice; however, the number of cagA copies decreased 8 weeks post infection, along with reduced pathogenic. We further showed that host adaptive immunity, probably Th1-IFN-γ, should be the key factor driving decrease of cagA copy number. Thus, we hypothesize that when Th1-IFN-γ immunity is hampered, Hp would keep high number of cagA copies and hence more virulent. In current study, we will first detail the process how change of cagA copy number regulates Hp pathogenicity in mice. Secondly, we will further confirm the key role of IFN-γ through multiple gene-engineered mice models and immune cell adoptive transfer. Finally, we will prove that when host adaptive immunity is impaired, Hp can keep high number of cagA copies and thus be more pathogenic. This study will clarify regulation of cagA copy number and conditions in which Hp keeps more cagA copies and be more virulent, providing evidence for Hp eradication and new clues for treatment of Hp related gastric diseases.