Identification and validation of novel virulence factors of Helicobacter pylori

幽门螺杆菌新型毒力因子的鉴定与验证

• 批准号: 12670459
• 负责人: YOSHIDA Haruhiko
• 金额: $ 2.18万
• 依托单位: THE UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670459/
• 关键词: Helicobacter pylori; CagA; cagPAI; Mongolian gerbil; intracellular signaling pathways; virulence; ヘリコバクタ・ピロリ; Cag PAI; 胃癌

First, we sought to confirm previously reported virulence factors, especially cagPAI. We compared anti-CagA antibody seropositivity between gastric cancer patients and matched controls by using recombinant CagA (a product of cagPAI) and found that anti-CagA positivity was associated with an odds ratio of 10 concerning gastric cancer. We also validated virulence of cagPAI in Mongolian gerbils using cagPAI gene knocked out mutants, showing that inflammation and tumorogenesis require cagPAI.Next, we investigated H. pylori-mediated induction of intracellular signaling pathways and demonstrated activation of NF-kappa B through IKK and TRAFs ; of SRE and AP-1 through the ERK cascade ; and of cyclin D1 through the MAPK cascade. The presence of cagPAI and direct contact between bacteria and host cells were required in the induction of those intracellular signals. We applied cDNA microarray analysis to examine various gene expressions in the host cells.Finally, we established a short-term Mongolian gerbil infection model to validate H. pylori virulence factors in vivo.

首先，我们试图确认以前报道的毒力因素，特别是cagPAI。我们用重组CagA(cagPAI的产物)比较了胃癌患者和对照组的抗CagA抗体阳性率，发现抗CagA阳性与胃癌的优势比为10有关。我们还利用cagPAI基因敲除突变体验证了cagPAI在蒙古沙土鼠中的毒力，表明炎症和肿瘤的发生需要cagPAI。接下来，我们研究了幽门螺杆菌介导的细胞内信号通路的诱导，证明了NF-kappa B通过ikk和traf激活；SRE和AP-1通过ERK级联激活；细胞周期蛋白D1通过MAPK级联激活。在诱导这些细胞内信号时，需要cagPAI的存在以及细菌和宿主细胞之间的直接接触。应用基因芯片技术检测宿主细胞中各种基因的表达，建立沙土鼠短期感染模型，验证幽门螺杆菌体内毒力因子的有效性。

项目成果

Mitsuno Y, et al.: "Helicobacter pylori induced transactivation of SRE and AP-1 through the ERK signaling pathway in gastric cancer cells"Gut. 49. 18-22 (2001)

Mitsuno Y 等人：“幽门螺杆菌通过胃癌细胞中的 ERK 信号通路诱导 SRE 和 AP-1 反式激活”Gut。

ogura U, Yoshida H et al.: "Clarithromychin-based triple therapy for non-resistant Helicobacter pylori infection : How long Should it be given ?"Scandinavian Journal of Gastroenterology. 36. 584-588 (2001)

ogura U、Yoshida H 等人：“基于克拉霉素的三联疗法治疗非耐药性幽门螺杆菌感染：应该给予多长时间？”《斯堪的纳维亚胃肠病学杂志》。

Ogura K, Maeda S, Nakao M, Watanabe T, Tada M, Kyutoku T, Yoshida H, Shiratori Y, Omata M: "Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil"Journal of Experimental Medicine. 192. 1601-1610 (2000)

Ogura K、Maeda S、Nakao M、Watanabe T、Tada M、Kyutoku T、Yoshida H、Shiratori Y、Omata M：“导致蒙古沙鼠胃部疾病的幽门螺杆菌毒力因子”实验医学杂志。

Maeda S, Otsuka M, Hirata Y, Mitsuno Y, Yoshida H, Shiratori Y, Masuho Y, Muramatsu M, Seki N, Omata M: "cDNA microarray analysis of Helicobacter pylori-mediated alteration of gene expression in gastric cancer cells"Biochemical and Biophysical Research Co

Maeda S、Otsuka M、Hirata Y、Mitsuno Y、Yoshida H、Shiratori Y、Masuho Y、Muramatsu M、Seki N、Omata M：“幽门螺杆菌介导的胃癌细胞基因表达改变的 cDNA 微阵列分析”生化和

Akanuma M, Maeda S, et al.: "The evaluation of putative virulence factors of Helicobacter pylori for gastroduodenal disease asing short-term Mongolian gerbil infection model"Journal of infectious Disease. 185. 341-347 (2002)

Akanuma M、Maeda S 等人：“作为短期蒙古沙鼠感染模型，评估幽门螺杆菌对胃十二指肠疾病的推定毒力因子”《传染病杂志》。