HOST AND BACTERIAL FACTORS IN DISEASE DUE TO H PYLORI

幽门螺杆菌引起的疾病的宿主和细菌因素

• 批准号: 2689786
• 负责人: KATHRYN A. EATON
• 金额: $ 20.71万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2689786
• 关键词: Helicobacter; SCID mouse; T lymphocyte; bacterial antigens; bacterial proteins; cytokine; disease /disorder proneness /risk; enzyme linked immunosorbent assay; gastritis; genetically modified animals; histology; host organism interaction; immunocytochemistry; immunoregulation; inflammation; laboratory mouse; mucosal immunity; virulence

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.

在其最极端的表现中，幽门螺杆菌可以负责 严重甚至威胁生命的疾病，从消化性溃疡到 胃癌。 尽管经常出现H.感染。 幽门螺杆菌，但是（某些人群中最多100％），严重 疾病的表现相对罕见。 只有少数 受感染的个体患上严重或临床意义的疾病。 确定单个宿主疾病严重程度的因素是 不知道。对这些因素的理解对于有效 但是，控制幽门螺杆菌相关疾病。 因为感染是 如此普遍，根除是不切实际的，因为大多数感染是 不能预测或 阻止。 因此，治疗和预防与 幽门螺杆菌需要理解确定的因素 疾病的严重程度。 该建议的目的是确定宿主和细菌因素 倾向于感染的个体的严重表现 疾病。 中心假设是与 幽门螺杆菌是由于粘膜免疫不受控制或失调 对特定细菌抗原的反应。 这些主机响应结果 在炎症和随后的组织损伤中，并负责 幽门螺杆菌感染的临床表现。 因此，两个主要 要解决的假设是：1）严重的疾病表现 是由于宿主免疫失调而引起的； 2）特定细菌 毒力因子诱导致病性免疫反应。 我们将测试 这些假设通过1）识别免疫细胞子集和细胞因子 参与胃炎（通过淋巴细胞的产物转移，原位 鉴定细胞和细胞因子，并评估依赖性 免疫小鼠突变体中T细胞和细胞因子上的胃炎），2） 确定特定细菌蛋白的作用（与CAG相关 蛋白质和其他）诱导致病宿主反应，并 3）确定这些蛋白质表达是否丧失（通过插入 或缺失诱变）与H的能力降低有关。 幽门螺杆菌在易感宿主中诱导严重疾病。