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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081037-04
Application #
8302361
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Mills, Melody
Project Start
2009-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$197,919
Indirect Cost
$60,064
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Barrozo, Roberto M; Cooke, Cara L; Hansen, Lori M et al. (2013) Functional plasticity in the type IV secretion system of Helicobacter pylori. PLoS Pathog 9:e1003189
Fei, Y Y; Schmidt, A; Bylund, G et al. (2011) Use of real-time, label-free analysis in revealing low-affinity binding to blood group antigens by Helicobacter pylori. Anal Chem 83:6336-41