HOST AND BACTERIAL FACTORS IN DISEASE DUE TO H PYLORI

在其最极端的表现中，幽门螺杆菌可以负责 严重甚至危及生命的疾病，从消化性溃疡到 胃癌。尽管霍乱弧菌感染频繁发生。 然而，幽门螺杆菌(在一些人群中高达100%)，严重 疾病的表现相对罕见。只有一小部分 受感染的人会发展成严重的或临床上严重的疾病。 决定单个宿主疾病严重程度的因素包括 不知道。对这些因素的理解对于有效地 然而，幽门螺杆菌相关疾病的控制。因为感染是 如此普遍，根除是不现实的，因为大多数感染是 疾病的亚临床、严重表现是无法预测的或 被阻止了。因此，治疗和预防与以下有关的疾病 幽门螺杆菌需要了解决定因素 疾病的严重性。 这项建议的目标是确定宿主和细菌因素 这使感染者容易出现严重的 疾病。中心假设是胃病与 幽门螺杆菌是由于粘膜免疫失控或失调所致 对特定细菌抗原的反应。这些主机响应导致 在炎症和随后的组织损伤中，并对 幽门螺杆菌感染的临床表现。因此，两个主要的 需要解决的假设是：1)严重的疾病表现 是由于宿主免疫失调所致；以及2)特定的细菌 毒力因子诱导病原性免疫反应。我们将测试 这些假设是通过1)确定免疫细胞亚群和细胞因子 参与胃炎(通过淋巴细胞过继转移，原位 细胞和细胞因子的鉴定和依赖性的评估 胃炎对免疫突变小鼠T细胞和细胞因子的影响)，2) 确定特定细菌蛋白的作用(CAG相关 蛋白质和其他)在致病宿主反应的诱导中，以及 3)确定这些蛋白的表达是否丢失(通过插入 或缺失突变)与H. 幽门螺杆菌在易感宿主中诱发严重疾病。

In its most extreme manifestations H. pylori can be responsible for severe and even life-threatening disease ranging from peptic ulcer to gastric cancer. In spite of the frequent occurrence of infection by H. pylori, however (up to 100 percent in some populations), severe manifestations of disease are relatively rare. Only a minority of infected individuals develop severe or clinically significant disease. The factors which determine disease severity in an individual host are not known. Understanding of these factors is vital to the effective control of H. pylori associated disease, however. Because infection is so common, eradication is not practical, and because most infections are subclinical, severe manifestations of disease cannot be predicted or prevented. Thus, treatment and prevention of disease associated with H. pylori necessitate understanding of the factors that determine disease severity. The goal of this proposal is to identify host and bacterial factors which predispose infected individuals to severe manifestations of disease. The central hypothesis is that gastric disease associated with H. pylori is due to uncontrolled or dysregulated mucosal immune responses to specific bacterial antigens. These host responses result in inflammation and subsequent tissue damage and are responsible for the clinical manifestations of infection by H. pylori. Thus, the two main hypotheses to be addressed are: 1) that severe manifestations of disease are due to dysregulated host immunity; and 2) that specific bacterial virulence factors induce the pathogenic immune response. We will test these hypotheses by 1) identifying the immune cell subsets and cytokines involved in gastritis (via adoptive transfer of lymphocytes, in situ identification of cells and cytokines, and evaluation of the dependence of gastritis on T cells and cytokines in immunologic mouse mutants), 2) determining the role of specific bacterial proteins (cag-related proteins and others) in induction of the pathogenic host response, and 3) determining if loss of expression of these proteins (by insertional or deletional mutagenesis) is associated with diminished ability of H. pylori to induce severe disease in a susceptible host.