GENETIC AND CELLULAR BASIS OF H. PYLORI PATHOGENESIS

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DESCRIPTION (Adapted from the Applicant's Abstract): The goal of the proposed research is to understand better the interaction between H. pylori and its human host. H. pylori is the causative agent of gastritis and ulcer disease, and infection is an important risk factor for the development of gastric cancer. In previous studies, these investigators have shown that H. pylori CagA is transported into the host cell, and is then phosphorylated on tyrosine residues by host cell kinase activity. The insertion of CagA into host cells and its subsequent phosphorylation is associated with reorganization of the host cell cytoskeleton, as well as a dramatic change in host cell morphology. The investigators propose to examine the insertion of CagA into host cells and the sequence of events following CagA insertion. In addition, they propose to alter the structure of CagA by mutagenesis to determine the role of specific protein domains in bringing about cellular changes. In a second phase of work, these investigators have obtained DNA arrays of the H. pylori genome and host gene arrays of both human and mouse genes. They propose to use the H. pylori DNA array to examine the genotype of clinical isolates from well-defined epidemiological studies to determine whether particular genes or groups of genes are associated with discrete clinical syndromes like ulcer disease or malignancy. The major thrust of the proposed work will focus on the use of DNA arrays to follow gene transcription of both bacterial and host genes during infection of polarized cultures of human epithelial cells. They hypothesize that this will permit the identification of new classes of virulence genes. The sequence of the host response as measured by gene transcription is suggested to permit better understanding of the host cell pathways that are exploited by the bacteria during infection. Finally, a method called microarray transposon tagged H. pylori (MATT) will be used, which permits the identification of specific classes of mutation from selective environments, including infected cell cultures and animals.