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 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 5'and 3'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. Studies in mice showed that BabA expression is also lost during experimental infection and the kinetics are similar to what is seen in macaques. We hypothesize that these modifications in H. pylori OMP expression represent a remodeling of the bacterial surface so as to avoid host immunity or promote attachment to the gastric epithelium.
Four Specific Aims are proposed to address this hypothesis.
Aim 1 will examine the immune response to purified BabA and BabB in H. pylori-infected macaques, in order to address the role of immune evasion in selection of H. pylori OMP expression.
In Aim 2 we will challenge macaques with wild type or isogenic mutant strains lacking babA or babB, and characterize the output strains as well as the host gene expression profile.
Aim 3 will exploit Rag-/- and Leb transgenic mice to better understand the role of adaptive immunity and Leb expression in modification of OMP expression.
In Aim 4 we will characterize BabB to determine whether it may function as a lectin to mediate H. pylori attachment, or, alternatively, as a protein that modulates BabA-mediated binding to blood group antigens. 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.
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.
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