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.
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