An anti-inflammatory protein of H. pylori: mechanism and diagnostic potential

描述（由申请人提供）：对于幽门螺杆菌如何控制宿主炎症，以及我们应该筛选哪些幽门螺杆菌基因产物来预测菌株的疾病潜力，我们的理解存在根本的空白。这种差距的持续存在使我们无法设计诊断工具，使我们能够预测哪些幽门螺杆菌感染将发展为疾病，因此，应该优先治疗。全世界和美国有数百万人感染了幽门螺杆菌，并患上了相关疾病——溃疡和胃癌。胃癌是全球癌症死亡的第二大原因。在美国，很少有人患胃癌，可能是由于幽门螺杆菌的发病率较低但稳定，这表明治愈幽门螺杆菌可能会降低癌症死亡人数。幽门螺杆菌感染仅在一小部分感染个体中发展为疾病。一个关键变量是菌株引发炎症的能力。我们研究的长期目标是创造准确的诊断方法，以确定哪些幽门螺杆菌菌株会引起麻烦。幽门螺杆菌菌株是高度可变的，这一特征为诊断测试提供了一个可能的入口和基础。我们最近的工作已经确定了一种新的抗炎幽门螺杆菌毒力因子，我们将其命名为免疫调节自转运蛋白a （ImaA）。我们的初步数据表明，缺乏imaA的幽门螺杆菌会触发哺乳动物细胞产生大量与炎症相关的mRNA和蛋白质。ImaA通过已知的幽门螺杆菌促炎器官cag PAI起作用，并且是促炎蛋白CagA持续磷酸化所必需的。这项工作的具体目的是确定ImaA对炎症的影响的分子基础，它对幽门螺杆菌疾病的贡献，以及它是否作为一种生物标志物

DESCRIPTION (provided by applicant): There is a fundamental gap in our understanding of how Helicobacter pylori controls host inflammation and, concomitantly, which H. pylori gene products we should screen to predict a strain's disease potential. Continued existence of this gap prevents us from designing diagnostic tools that would allow us to predict which H. pylori infections will progress to disease, and therefore, should be high priorities to cure. Millions of people worldwide and in the U.S. are infected by H. pylori and suffer from its associated diseases-ulcers and gastric cancer. Gastric cancer is the second cause of cancer deaths worldwide. In the U.S., fewer people have gastric cancer likely due to lower but stabilized H. pylori incidence, underlying the idea that curing H. pylori would probably lower the number of cancer deaths. H. pylori infection progresses to disease in only a subset of infected individuals. A key variable is a strain's ability to drive inflammation. The long-term goal of our research is create accurate diagnostics that identify which H. pylori strains will cause trouble. H. pylori strains are highly variable, and this feature offers a possible entr¿e to--and basis for--diagnosti tests. Our recent work has identified a novel anti-inflammatory H. pylori virulence factor, which we named immunomodulatory autotransporter A (ImaA). Our preliminary data show that H. pylori that lack imaA trigger mammalian cells to produce large amounts of inflammation-associated mRNA and protein. ImaA acts through the known H. pylori proinflammatory apparatus, the cag PAI, and is required for sustained phosphorylation of the proinflammatory protein CagA. The specific objective of this work is to determine the molecular basis for ImaA's effect on inflammation, its contribution to H. pylori disease, and whether it serves as a biomarker for severe H. pylori human infections. Our central hypothesis is that ImaA acts to manipulate host phosphorylation of the proinflammatory protein CagA, and that loss of imaA creates H. pylori that cause especially severe disease in gerbils and humans. In the first Aim, we will determine the molecular mechanism by which H. pylori ImaA diminishes cag PAI-dependent pro-inflammatory gene expression. In the second Aim, we will probe how the anti-inflammatory protein ImaA impacts illness by analyzing how loss of imaA affects disease in a relevant animal model and by testing whether the presence of imaA correlates with inflammation and disease outcome in a panel of H. pylori human clinical strains. The proposed research is significant because it will give us a better understanding of the proteins used by H. pylori to control inflammation, and give us another tool with which to probe a particular H. pylori strain's disease potential. The proposed research is innovative in the hypothesis to be tested: that H. pylori produces anti-inflammatory as well as pro-inflammatory proteins. Ultimately the proposed work will inform us about how a new type of virulence factor functions, as well as how it will serve as a disease biomarker and advance our ability to prevent ulcers and gastric cancer.