Helicobacter pylori (H. pylori) is a bacterium that infects 20% and 70% of the population in developed and developing countries, respectively. Although most infections are asymptomatic, repeated inflammation resulting from chronic infection drives gastritis, ulcers, and favors gastric cancer. The helical shape of the bacterium, combined with the presence of flagella, ensures high motility to escape the extremely acidic environment in the stomach. After navigating within the mucus covering the stomach lining, the bacterium infiltrates the epithelial layer of the corpus (central part of the stomach) and the antrum (terminal part of the stomach, before the duodenum). Although it is known that H. pylori’s helical cell shape promotes the motility in the mucus layer with corkscrew-like motion, the role of this shape in tissue infiltration and pathogenicity is still unclear. This is a question the Salama lab (Human Biology division) started to address in a work recently published in Infection and Immunity.
Dr. Laura Martinez and colleagues studied a straight rod mutant strain of H. pylori that lacks the Csd6 enzyme (Deltacsd6), resulting in a loss of the helical shape. Two methods were used to follow the kinetics of the infection in the stomach, comparing the Deltacsd6 mutant to the isogenic wild-type strain. First, the researchers counted the number of colonies forming in a culture of H. pylori extracted from the stomach. The second method used an in situ volumetric measurement of the number of bacteria in the gastric mucosa. Reconstruction of 3D images from confocal images across a thick slice of tissue enabled localizing and counting bacteria. Both methods demonstrated that Deltacsd6 mutants colonize the gastric mucosa less efficiently than WT bacteria up to a week after infection, although both strains preferentially infiltrate the antrum compared to the corpus.
When assessing the behavior of mutant and WT H. pylori in a chronic infection setting (one and three months post infection), the researchers were surprised to observe a similar colonization of the gastric mucosa by both strains, suggesting that the helical shape of H. pylori does not play a role in bacterial expansion once in the tissue. However, analysis of the mucosal inflammation resulting from chronic infection revealed a significant decrease of inflammatory parameters when the epithelium was infected by Deltacsd6 mutants. As Dr. Salama explains, these results intrigued the team: “Laura and I had fully expected that the straight mutants would have difficulty penetrating the gastric glands and thus might produce less inflammation. Instead we found that the mutants have a subtle delay, but at later timepoints get down into the gastric glands as well or better than wild-type. In spite of being able to get up close and personal with stomach tissues, the straight mutants induce less inflammation. This result is really surprising. Other work in both H. pylori and other bacteria (Campylobacter jejuni, Vibrio cholerae) have supported a paradigm where it is the ability to penetrate the mucus and get to the gland or crypt that governs inflammation induction via chemotaxis and other cell behaviors. This work shows that helical cell shape governs not only the ability to efficiently colonize the stomach, but how the bacterium interacts with the host tissues. Future work will be needed to explore the specifics of the different interaction with cells.”
For the Salama lab, the discovery that this Deltacsd6 strain is much less pathogenic than the WT strain albeit similarly colonizing the mucosa opens interesting therapeutic options. “We are now curious whether infection with this less inflammatory strain could alter the host response to superinfection with a wild-type helical strain,” Salama said. “If this were true, the straight mutants might be used as a prebiotic. This is because infections that cause high inflammation are the ones at risk for developing disease (cancer and ulcer). If we could change the inflammatory balance, we might be able to reduce the incidence of H. pylori associated diseases.”
This work was supported by the National Institute of Health.
Fred Hutch/UW Cancer Consortium member Dr. Nina Salama contributed to this research.
Martínez LE, O’Brien VP, Leverich CK, Knoblaugh SE, Salama NR. Non-helical Helicobacter pylori show altered gland colonization and elicit less gastric pathology during chronic infection. Infect. Immun. 2019. doi:10.1128/IAI.00904-18.
Basic Sciences Division
Human Biology Division
Maggie Burhans, Ph.D.
Public Health Sciences Division
Vaccine and Infectious Disease Division
Clinical Research Division
Julian Simon, Ph.D.
Clinical Research Division
and Human Biology Division
Arnold Digital Library