Abstract: Helicobacter pylori chronically infects 50% of the world’s population and is a significant cause of gastric cancer. In the stomach, the bacterium interacts with host cells and elaborates virulence factors that directly influence disease etiology. To maintain colonization within this niche, H. pylori needs mechanisms to withstand mechanical clearance during the sloughing of epithelial cells and mucous, as well as mechanisms to prevent detection and clearance by the immune system. Genes encoding for outer membrane proteins (OMPs) constitute approximately 4% of the H. pylori genome, and it is likely that this extensive array of proteins may play a crucial role in establishing and maintaining infection by aiding in adhesion and/or immune evasion. Thus, the OMPs likely serve as key elements of the host-bacterium interface. In addition, several variable OMPs have been shown to be associated with more severe disease presentations such as gastric ulcers and gastric cancer. Included among these virulence-associated OMPs is Helicobacter Outer Membrane Protein B (HomB). HomB is highly similar to HomA and the two have been shown to have the ability to occupy two primary loci, locus A and locus B in the H. pylori genome; some strains carry both genes, while some carry one or the other. There are no studies that address the implications of the two possible genomic locations for homA and homB. Furthermore, despite the fact that in vitro studies indicate a role for HomB in adherence, virtually no other molecular studies have been conducted to assess the role of HomA and HomB during H. pylori infection. To gain a better understanding of the expression and function of these two OMPs, we propose detailed molecular studies that will directly examine expression of homA and homB in response to environmental stresses that mimic those found within the gastric environment. Furthermore, using a series of constructed isogenic mutant and complementation strains that carry all possible single gene combinations of homA and homB, we will directly assess the role of HomA and HomB in colonization and disease progression in the Mongolian gerbil model of infection. The described studies will provide novel information concerning expression and function of HomA and HomB. This information may in turn provide clues to the development of novel therapeutics that are designed to specifically target these OMPs.