GENETICS AND CELLULAR BASIS OF H PYLORI PATHOGENESIS

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Helicobacter pylori infects nearly half of the world's population, especially in developing countries paralleled by rates of gastric cancers, a leading cause of malignancy in some countries, and peptic ulcer disease. Significant epidemiological and biological evidence suggests that H. pylori infection is a necessary risk factor for the development of gastric cancer and peptic ulcers. Little is known about the bacterial factors that permit H. pylori to infect gastric tissue or those gene products that bring about the state of chronic, persistent inflammation that accompanies infection and gastric diseases. As well, the response of host cells to H. pylori infection has not been defined. We propose two broad specific aims to elucidate the nature of the interaction between the pathogen and the host: 1) to define the contribution of H. pylori virulence factors to the molecular and cell biology of the interaction with host cells; and 2) to define the biological consequences to the host cell associated with the attachment and subsequent stable infection by H. pylori to cellular targets. We will utilize unique methods of video and confocal microscopy to study Intracellular trafficking and response of host cells to Infection, and we will exploit novel molecular methods to identify new bacterial genes that are environmentally regulated and expressed in vivo. In addition, we propose to utilize a molecular method known as differential display to study the effect of viable bacteria and bacterial factors on eukaryotic cells. Previous studies in our laboratories on H. pylori and other enteric pathogens utilizing these approaches have provided the relevant experience and have produced exciting insights into the biological consequences of the host-pathogen interaction. Thus, we expect that a similar approach to understand the pathogenesis of Helicobacter infection will be fruitful.