The Role of CagA in the Gastric Biology of Helicobacter pylori.
The Role of CagA in the Gastric Biology of Helicobacter pylori.
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DOI：
10.1158/0008-5472.can-16-1680
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发表时间：
2016-07-15
期刊：
影响因子：
11.2
通讯作者：
Blaser MJ
中科院分区：
文献类型：
--
作者：
Backert S;Blaser MJ
幽门螺杆菌是由澳大利亚科学家沃伦和马歇尔于1983年发现的一种引起消化性溃疡的胃部病原体。2005年，他们因自己的发现获得了诺贝尔医学奖或生理学奖，特别是因为使用抗生素治疗溃疡改变了医学实践。20世纪90年代初，我们的团队和其他人表明，幽门螺杆菌也与导致胃癌有关。在溃疡和癌症之间，幽门螺杆菌已经成为人类的主要病原体。然而，幽门螺杆菌的定植在世界范围内非常普遍，影响到世界上大约一半的人口，而且大多数携带者既不会患溃疡，也不会患癌症。因此，我们一直在调查某些菌株是否可能比其他菌株更具致病性。从1988年到1989年，我的实验室正在创建幽门螺杆菌基因库，以识别和克隆重要的抗原。使用幽门螺杆菌携带者(MJ布拉泽)的血清对这些文库进行筛选，发现了一个免疫活性很强的克隆，我们最终对其进行了鉴定。同时，我们询问携带者是否对特定的细菌蛋白产生抗体反应，包括分泌的空泡细胞毒素(VacA)。1990年，我们报道了携带真空菌株的人产生了一条约128 kDa的抗体，而没有毒素活性的菌株的携带者中没有这种抗体[1]。我们的两种方法都鉴定出了完全相同的蛋白质，我们和锡耶纳的同事后来联合将其命名为细胞毒素相关基因A(cagA和由此产生的蛋白质CagA；参考文献)。2、3)。1991年，Jean Crabtree和她的同事在英国发表的研究报告证实了我们早先发现的一种高分子量蛋白质(他们测量它的大小为120 kDa)与消化性溃疡疾病之间的联系。另一个团队在大洋彼岸，使用平行但不同的研究方法，得出了基本上完全相同的结果，这一独立确认为我们证实了我们正在研究一些重要的东西。1995年，我们在《癌症研究》杂志上报道，携带CAGTOA菌株与胃癌风险增加有关(5)，也就是我们今天记住的那篇文章，但这只是涉及世界各地多名科学家的长链研究中的一个环节。1995年，我们也报道了细菌染色体上与cagA相邻的一个与IV型分泌系统(T4SS)蛋白(Cage或virB4)同源的基因，该基因的突变消除了CagA对上皮细胞的主要影响[6]，但在这个阶段，我们并不了解这一过程的所有步骤。之后
Helicobacter pylori (H. pylori) was discovered in 1983 by the Australian scientists Warren and Marshall as a gastric pathogen, causing peptic ulcer disease. In 2005, they received the Nobel Prize in Medicine or Physiology for their discoveries, especially because the use of antibiotics to treat ulcers changed the practice of medicine. In the early 1990s, our group and others showed that H. pylori is also involved in causing gastric cancer. Between ulcers and cancer, H. pylori became firmly established as a major human pathogen. Yet, colonization by H. pylori is extremely common worldwide, affecting about half of the world's population, and most carriers develop neither ulcers nor cancer. As such, we had been investigating whether some strains might be more pathogenic than others. In 1988 to 1989, my laboratory was creating libraries of H. pylori genes to identify and clone important antigens. A screen of these libraries using serum from an H. pylori carrier (MJ Blaser) identified a strongly immunoreactive clone, which we ultimately characterized. Concurrently, we were asking whether carriers developed antibody responses to specific bacterial proteins, including the secreted vacuolating cytotoxin (VacA). In 1990, we reported that people carrying VacA þ strains produced antibodies to a band at about 128 kDa that was absent in carriers of strains that did not have toxin activity (1). Both of our approaches identified the very same protein, which we and colleagues in Siena later jointly named as cytotoxin-associated gene A (cagA and the resulting protein CagA; refs. 2, 3). Studies reported in 1991 by Jean Crabtree and her colleagues in England confirmed our earlier association of a high molecular weight protein (they measured it at 120 kDa) with peptic ulcer disease (4). That independent confirmation by another team, across an ocean, using parallel but different investigative methods, showing essentially the exact same result, confirmed for us that we were on the track of something important.In 1995, we reported in Cancer Research that carriage of a CagA þ strain was associated with increased risk of gastric cancer (5), that is, the article we are remembering today, but it was one link in a long chain of studies involving multiple scientists around the world. In 1995, we also reported that adjacent to cagA on the bacterial chromosome was a homolog to a type IV secretion system (T4SS) protein (cagE or virB4), and mutating that gene eliminated major CagA effects on epithelial cells (6), but at this stage we did not understand all of the steps in the process. After