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Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence.

ABSTRACT: The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

SUBMITTER: Bugaytsova JA

PROVIDER: S-EPMC5392239 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence.

Bugaytsova Jeanna A JA Björnham Oscar O Chernov Yevgen A YA Gideonsson Pär P Henriksson Sara S Mendez Melissa M Sjöström Rolf R Mahdavi Jafar J Shevtsova Anna A Ilver Dag D Moonens Kristof K Quintana-Hayashi Macarena P MP Moskalenko Roman R Aisenbrey Christopher C Bylund Göran G Schmidt Alexej A Åberg Anna A Brännström Kristoffer K Königer Verena V Vikström Susanne S Rakhimova Lena L Hofer Anders A Ögren Johan J Liu Hui H Goldman Matthew D MD Whitmire Jeannette M JM Ådén Jörgen J Younson Justine J Kelly Charles G CG Gilman Robert H RH Chowdhury Abhijit A Mukhopadhyay Asish K AK Nair G Balakrish GB Papadakos Konstantinos S KS Martinez-Gonzalez Beatriz B Sgouras Dionyssios N DN Engstrand Lars L Unemo Magnus M Danielsson Dan D Suerbaum Sebastian S Oscarson Stefan S Morozova-Roche Ludmilla A LA Olofsson Anders A Gröbner Gerhard G Holgersson Jan J Esberg Anders A Strömberg Nicklas N Landström Maréne M Eldridge Angela M AM Chromy Brett A BA Hansen Lori M LM Solnick Jay V JV Lindén Sara K SK Haas Rainer R Dubois Andre A Merrell D Scott DS Schedin Staffan S Remaut Han H Arnqvist Anna A Berg Douglas E DE Borén Thomas T

Cell host & microbe 20170301 3

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA ...[more]

PMID: 28279347

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Project description:UNLABELLED:Helicobacter pylori undergoes rapid microevolution during chronic infection, but very little is known about how this affects host interaction factors. The best-studied adhesin of H. pylori is BabA, which mediates binding to the blood group antigen Lewis b [Le(b)]. To study the dynamics of Le(b) adherence during human infection, we analyzed paired H. pylori isolates obtained sequentially from chronically infected individuals. A complete loss or significant reduction of Le(b) binding was observed in strains from 5 out of 23 individuals, indicating that the Le(b) binding phenotype is quite stable during chronic human infection. Sequence comparisons of babA identified differences due to mutation and/or recombination in 12 out of 16 strain pairs analyzed. Most amino acid changes were found in the putative N-terminal extracellular adhesion domain. One strain pair that had changed from a Le(b) binding to a nonbinding phenotype was used to study the role of distinct sequence changes in Le(b) binding. By transformations of the nonbinding strain with a babA gene amplified from the binding strain, H. pylori strains with mosaic babA genes were generated. Recombinants were enriched for a gain of Le(b) binding by biopanning or for BabA expression on the bacterial surface by pulldown assay. With this approach, we identified several amino acid residues affecting the strength of Le(b) binding. Additionally, the data showed that the C terminus of BabA, which is predicted to encode an outer membrane ?-barrel domain, plays an essential role in the biogenesis of this protein. IMPORTANCE:Helicobacter pylori causes a chronic infection of the human stomach that can lead to ulcers and cancer. The bacterium can bind to gastric epithelial cells with specialized outer membrane proteins. The best-studied protein is the BabA adhesin which binds to the Lewis b blood group antigen. Since H. pylori is a bacterium with very high genetic variability, we asked whether babA evolves during chronic infection and how mutations or recombination in babA affect binding. We found that BabA-mediated adherence was stable in most individuals but observed a complete loss of binding or reduced binding in 22% of individuals. One strain pair in which binding was lost was used to generate babA sequences that were mosaics of a functional allele and a nonfunctional allele, and the mosaic sequences were used to identify amino acids critically involved in binding of BabA to Lewis b.

Dataset Information

Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence.

Publications

Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence.

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