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Mechanisms of disease: Helicobacter pylori virulence factors

Abstract

Helicobacter pylori plays an essential role in the development of various gastroduodenal diseases; however, only a small proportion of people infected with H. pylori develop these diseases. Some populations that have a high prevalence of H. pylori infection also have a high incidence of gastric cancer (for example, in East Asia), whereas others do not (for example, in Africa and South Asia). Even within East Asia, the incidence of gastric cancer varies (decreasing in the south). H. pylori is a highly heterogeneous bacterium and its virulence varies geographically. Geographic differences in the incidence of gastric cancer can be explained, at least in part, by the presence of different types of H. pylori virulence factor, especially CagA, VacA and OipA. However, it is still unclear why the pathogenicity of H. pylori increased as it migrated from Africa to East Asia during the course of evolution. H. pylori infection is also thought to be involved in the development of duodenal ulcer, which is at the opposite end of the disease spectrum to gastric cancer. This discrepancy can be explained in part by the presence of H. pylori virulence factor DupA. Despite advances in our understanding of the development of H. pylori-related diseases, further work is required to clarify the roles of H. pylori virulence factors.

Key Points

  • Experimental evidence suggests that East-Asian-type CagA is more virulent than Western-type CagA, but the concept that this explains geographic differences in the incidence of gastric cancer is still controversial

  • The number of CagA Glu-Pro-Ile-Tyr-Ala (EPIYA)-C segments (with multiple repeats increasing the virulence) may explain, to some extent, geographic differences in the incidence of gastric cancer in Western countries

  • The genotype of the vacA middle region (m1 versus m2; m1 being more virulent) may, in part, explain geographic differences in the incidence of gastric cancer in East Asian countries

  • CagA, OipA and VacA are thought to interact synergistically with each other to induce serious disease

  • The presence of functional DupA with an intact, full size dupA cluster (tfs3a) is associated with duodenal ulcers

  • Bacterial factors, environmental factors and host factors are thought to form complex interactions with each other in the actual development of disease

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Figure 1: Distribution of Helicobater pylori genotypes before Columbus found the New World and human migration to America and Oceania began.
Figure 2: Structural polymorphism in CagA.
Figure 3: The pathogenesis of CagA-related signaling.
Figure 4: The pathogenesis of OipA-related signaling.
Figure 5: Type IV secretion system in the Helicobacter pylori plasticity zone.

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Acknowledgements

This report is based on work supported in part by grants from the NIH (DK62813), and grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (22390085 and 22659087).

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Yamaoka, Y. Mechanisms of disease: Helicobacter pylori virulence factors. Nat Rev Gastroenterol Hepatol 7, 629–641 (2010). https://doi.org/10.1038/nrgastro.2010.154

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