Genome sequencing of numerous prokaryotes has revealed a tendency toward decreased genetic investment in signal transduction machinery in species that exist in restricted ecological niches. Bacterial signal transduction systems are typically comprised of a sensory histidine kinase protein and a cognate transcription factor, known as a response regulator. Bacterial species capable of growth in multiple environments have large numbers of signal transduction systems, as many as 63 separate systems. Bacteria that are restricted to a pathogenic lifestyle and have no known environmental reservoir possess many fewer systems to detect and respond to environmental changes. Helicobacter pylori, the etiologic agent of peptic ulcer disease as well as gastric adenocarcinoma, appears to inhabit exclusively the human gastric mucosa. Genome sequencing of this bacterium reveals only 4 signal transduction pathways. This implies a somewhat limited repetoire of signals to which this pathogen can respond. This proposal takes advantage of the complete genetic characterization of two distinct pathogenic strains of H. pylori to examine the role of one specific signal transduction system in the control of gene expression. The studies described here will facilitate the determination of signals in the gastric ecosystem that serve as cues for H. pylori to alter its gene expression pattern. This will be accomplished by identifying genes used in the adaptive response to these environmental signals. These studies will utilize H. pylori mutants which are """"""""blinded"""""""" to an aspect of their environment due to the targeted destruction of genes encoding a sensory protein. Utilizing whole-genome transcriptional profiling by means of DNA microarrays, the regulatory events comprising the adaptive response in this gastric pathogen will be mapped and the genes of the adaptive response will be characterized. Determination of the identity of genes whose transcription is regulated will allow potential environmental cues to be inferred and then experimentally determined. Similarly, use of recombinant transcription factors (response regulators) will allow the isolation of critical DNA sequences necessary to accomplish regulation of gene expression. Understanding of the gastric environment, as perceived though the sensory apparatus of H. pylori, will allow a better understanding of H. pylori pathogenesis and a more rational design of interventions into the infectious process.
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