Salama, colleagues unlock ulcer bug’s structure
The corkscrew-shaped bacterium Helicobacter pylori lives in the human stomach and is associated with ulcers and gastric cancer. For years, researchers have hypothesized that the bacterium’s twisty shape is what enables it to survive—and thrive—within the stomach’s acid-drenched environment, but until now they have had no proof.
For the first time, Center researchers have found that, at least when it comes to H. pylori’s ability to colonize the stomach, shape indeed matters. Dr. Nina Salama, a microbiologist in the Human Biology Division, and colleagues reported their findings May 28 in Cell.
Salama and colleagues are the first to demonstrate that the bug’s helical shape helps it set up shop in the protective gelatin-like mucus that coats the stomach. Such bacterial colonization—present in up to half of the world’s population—causes chronic inflammation that is linked to a variety of stomach disorders, from chronic gastritis and duodenitis to ulcers and cancer.
“By understanding how the bug colonizes the stomach, we can think about targeting therapy to prevent infection in the first place,” Salama said. The paper’s first author, Dr. Laura Sycuro, conducted this work while a student in the University of Washington/Hutchinson Center Molecular and Cellular Biology graduate program. She is now a postdoctoral research associate in the Clinical Research Division.
Specifically, the researchers discovered a group of four proteins that are responsible for generating H. pylori’s characteristic curvature. Using a mouse model, they found that laboratory-engineered mutant strains of H. pylori that are deficient in these proteins fail to twist properly and, consequently, are unable to colonize the stomach.
The researchers also discovered a novel mechanism by which these proteins drive the organism’s shape, in essence acting like wire cutters on a chain-link fence to strategically snip certain sections, or crosslinks, of the bacterium’s mesh-like cell wall. “The crosslinks preserve the structural integrity of the bacterial wall, but if certain links are cleaved or relaxed by these proteins, it allows the rod shape to twist into a helix,” Salama said.
Mutant forms of H. pylori that lack these proteins are misshapen, ranging from rods to crescents, which hampers their ability to bore through or colonize the stomach lining.
“We found that the bacteria that lost their normal shape did not infect well, and so we know that if we inhibit normal shape we can slash infection rates,” Salama said.
Other disease-inducing bacteria that have these proteins include Vibrio cholerae, a comma-shaped bug that causes cholera, and the curved to helical rod-shaped Campylobacter jejuni, which is the leading cause of bacterial diarrhea in developed countries.
“The fact that we found proteins that act on the cell wall of H. pylori that seem to be important for bacterial survival and that these proteins are found in other pathogens with similar shapes makes them a possible drug target for a number of bacterial diseases,” she said.
H. pylori is contagious, but its exact transmission route is unknown. While more than 80 percent of those infected will remain asymptomatic, an estimated 10 percent to 15 percent will develop related diseases such as ulcers and/or stomach cancer. About 70 percent of stomach cancers are associated with H. pylori infection.
The current treatment for H. pylori infection in those diagnosed with peptic ulcers includes antibiotics to eradicate the bug. Such treatment is not always effective, however, due to antibiotic resistance.
The National Institutes of Health and the National Science Foundation funded this research, which also involved investigators from Yale University and Newcastle University.
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