Role of H. pylori Outer Membrane Proteins in Colonization and Host Response

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DESCRIPTION (provided by applicant): Helicobacter pylori commonly infects the stomach, where it causes inflammation (gastritis) in all individuals and peptic ulcer disease or gastric cancer in some. H. pylori attachment to the gastric epithelium is mediated by a large family of outer membrane proteins (OMPs), the best studied of which is BabA, the Lewis b (Leb)/ABO blood group binding adhesin. BabA is clinically relevant because patients infected with strains that express it are more likely to develop peptic ulcer or gastric cancer. A closely related protein, BabB, shows extensive homology with BabA, but its function is unknown. We recently showed that H. pylori strains recovered from experimentally infected macaques had lost expression of BabA. In some cases the babA gene was replaced by babB (an apparent gene conversion event) and in other cases the babA gene was not expressed due to alteration in the number of dinucleotide CT repeats in the 5' coding region. Strains lacking BabA expression did not adhere to the Leb blood group antigen that is expressed on rhesus gastric epithelium. Analysis of human clinical strains showed that many patients are infected with variants of H. pylori whose OMP profile resembles that seen in macaques. Since BabA expression is also lost during experimental infection of both wild type and Rag-/- mice, evasion of adaptive immunity is probably not playing a role. We hypothesize that modifications in H. pylori OMP expression represents a remodeling of the bacterial surface so as to avoid innate host immunity and promote attachment to the gastric epithelium. Four Specific Aims are proposed to address this hypothesis. Aim 1 will determine the effect of BabA and BabB on host response and modulation of OMP expression during H. pylori infection of rhesus macaques. In Aim 2 we will determine the competitive effect of BabA and BabB on H. pylori colonization of rhesus macaques. Aim 3 will examine the role of affinity of BabA binding to Leb on the expression of BabA. In Aim 4 we will characterize the role of BabB in H. pylori attachment. These studies of BabA and BabB will contribute to ongoing translational research that seek to investigate the use of BabA and BabB as vaccine candidates, and also may have broad implications for the role of genome diversity in promoting chronic infection with H. pylori. PUBLIC HEALTH RELEVANCE: Helicobacter pylori is a bacterial pathogen that commonly infects the human stomach and sometimes causes peptic ulcers or gastric cancer. One factor that determines whether infection causes disease, or just asymptomatic colonization, is the particular profile of surface proteins that mediate attachment to the gastric epithelium. This project seeks to understand some of the factors that determine the expression of these surface proteins in H. pylori.