Diversity’s Double-Edged Sword
H. pylori’s attachment protein allows it to adhere to multiple blood group antigens – but also contains a disulfide-clasped loop that may be its downfall
Helicobacter pylori is a well-known culprit in cases of gastritis, peptic ulcer and gastric cancer. The bacterium is able to survive the acidic stomach environment by attaching itself tightly to the epithelial cells of the gastric mucosa – a key mechanism in the establishment of chronic infection and mucosal inflammation. In the 90s, Borén identified the ABO blood group antigens as binding sites for the H. pylori BabA adhesin in the gastric cell lining (1)(2). Vaccine development has so far shown limited progress, and although H. pylori is one of the most prevalent infection in humans, antibiotic therapy is restricted because of the risk of resistance and therefore only recommended for use against peptic ulcers. With no way of identifying the patients at greatest risk of stomach cancer, and only poor ways of fighting the disease once it develops, there’s an urgent need to develop new therapies against H. pylori infection. Fortunately, a team of researchers in Belgium and Sweden have uncovered what they deem the bacterium’s Achilles heel: a weakness in the binding protein BabA (3).
Thomas Borén, who led the Swedish contingent, explains that BabA binds to the ABO blood group glycans presented on the gastrointestinal epithelial cells (4): “In the stomach, H. pylori manage to adapt extensively to changes in the stomach such as during chronic inflammation.” He and his team have determined that BabA is extensively polymorphic due to adaptation (4). By crystallization of the protein, Han Remaut’s team in Brussels could show that the functional polymorphism is owing to two diversity loops inside the protein’s glycan binding site, whose amino acid sequences can be changed to alter binding properties, such as blood group preference. But at the same time, the teams discovered that the binding “holdfast” in the BabA protein is formed by a disulfide-clasped loop that can be inactivated by reduction – providing hopes that the source of the bacterium’s strength may also be the source of its defeat.
“The possibilities we now have uncovered to specifically interfere with H. pylori adherence and reduce the intensity of the chronic inflammation processes are exceedingly exciting,” says Remaut, “especially since this does not involve the use of broad-range antibiotics that are known to have undesired collateral impact on the healthy microbiota.” Instead, the two teams propose to treat infections using redox-active drugs that inactivate the disulfide-clasped loop, causing difficulties only to H. pylori (see Figure 1). “This could open the door to a new type of antimicrobial drugs,” says Remaut. “The structural information also provides promising possibilities for how to develop novel vaccines against adherent H. pylori infections, says Borén. The two teams are currently studying the way H. pylori adapts to changes in the stomach during disease progression, and they anticipate that better understanding of the H. pylori attachment processes will also help epidemiological studies. MS
Figure 1. Close up view of the BabA protein’s glycan binding site in complex with Lewis B, its main blood group antigen receptor in the stomach epithelium. Shown is a superimposition of the BabA proteins from four clinical isolates, highlighting the diversity inside the binding pocket. Redox-active pharmaceuticals such as N-Acetylcysteine (NAC) disrupt the conserved cys-clasped loop in the binding pocket (boxed area), and lead to the loss of H. pylori adherence to the stomach epithelium (see bar graph).
- T Borén et al., “Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens”, Science, 262, 1892–1895 (1993). PMID: 8018146.
- D Ilver et al., “Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging”, Science, 16, 373–377 (1998). PMID: 9430586.
- K Moonens et al., “Structural insights into polymorphic ABO glycan binding by Helicobacter pylori”, Cell Host Microbe, 19, 55–66 (2016). PMID: 26764597.
- M Aspholm-Hurtig et al., “Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin”, Science, 23, 519–522 (2004). PMID: 15273394.
While obtaining degrees in biology from the University of Alberta and biochemistry from Penn State College of Medicine, I worked as a freelance science and medical writer. I was able to hone my skills in research, presentation and scientific writing by assembling grants and journal articles, speaking at international conferences, and consulting on topics ranging from medical education to comic book science. As much as I’ve enjoyed designing new bacteria and plausible superheroes, though, I’m more pleased than ever to be at Texere, using my writing and editing skills to create great content for a professional audience.
