Salama, NinaCohen, Ilana Emily2014-10-132014-10-132014-10-132014Cohen_washington_0250E_13236.pdfhttp://hdl.handle.net/1773/26382Thesis (Ph.D.)--University of Washington, 2014<italic>Helicobacter pylori</italic> chronically colonizes the stomachs of approximately 50% of the world's population, with outcomes ranging from gastritis to ulcers and gastric cancer. <italic>H. pylori</italic> is genetically diverse both across and within infected individuals. This diversity can be generated by a variety of mechanisms, including mutation and recombination, and strains can exchange DNA through natural competence. The bacterial genetic changes that occur during the course of chronic infection are thought to adapt the organism to its niche at the gastric epithelial surface. Transmission from person to person is primarily among family members or close household contacts. Transmitted strains retain close genetic relatedness, but transmission may also be accompanied by bacterial genetic changes that have not been extensively studied at the whole genome level. Here, <italic>H. pylori</italic> transition to a new host or environment has been modeled by adaptation of the bacteria to infect mice, as well as to grow under laboratory culture conditions. Whole genome sequencing of <italic>H. pylori</italic> isolates adapted to novel host conditions revealed an overrepresentation of mutations in genes related to the cell envelope, including outer membrane proteins. Isogenic mutants in <italic>H. pylori</italic> genes altered during murine adaptation revealed the dominant role of a loss of function mutation in <italic>imc1</italic>, encoding a previously-uncharacterized protein here denoted Inhibitor of mouse colonization, on murine colonization potential. Imc1 was found to be associated with the <italic>H. pylori</italic> cell envelope and may influence adherence to murine gastric epithelial cells. A loss of function mutation in <italic>cagY</italic>, encoding a component of the <italic>cag</italic> type IV secretion system, abrogated delivery of bacterial factors into host cells by <italic>H. pylori</italic> adapted for persistent murine infection. <italic>H. pylori</italic> selected for interaction with host cells in culture were found to have undergone recombination with a distinct wild type strain, among other mutations. Repeated passaging in liquid culture resulted in changes in genes involved in nutrient uptake and growth. Although many of the identified mutations remain to be characterized, this dissertation lays the groundwork for a more complete understanding of the changes required for <italic>H. pylori</italic> adaptation to new conditions.application/pdfen-USCopyright is held by the individual authors.genetics; Helicobacter pylori; host adaptation; mouse; sequencingMicrobiologyGeneticsMolecular biologymolecular and cellular biologyThesis