Helicobacter pylori is a major human pathogen that is responsible for diseases, such as duodenal ulcer, gastric ulcer, and gastric cancer. It is a spiral-shaped gram-negative rod with 4-6 polar sheathed flagella which resides on the luminal surface of the gastric epithelium of humans.
H. pylori is classified as a group I carcinogen and is regarded as a primary factor for gastric cancer development.
New infections with H. pylori are thought to occur as a consequence of direct human-to-human transmission, via oral-oral or fecal-oral or both routes. Colonization with H. pylori is not a disease in itself but both gastric and duodenal ulcer diseases are strongly related to H. pylori. Among infected individuals, the outcome of the infection is influenced by the virulence of the infecting H. pylori strain, genetic susceptibility of the host and environmental co-factors.
Marshall and Warren first isolated Helicobacter pylori in 1983.
To date, a number of virulence factors of Helicobacter pylori have been identified and characterized. Some of the major virulence factors of H. pylori and their role will be discussed in this blog.
H. pylori contains multiple, polar sheathed flagella responsible for its corkscrew motility. The flagella confer motility and allow rapid movement in viscous solutions such as the mucus layer overlying the gastric epithelial cells and helps in colonization.
Urease is an important virulence factor for H. pylori. H. pylori urease metabolizes urea producing ammonia (NH3) and carbon dioxide (CO2). Ammonia counteracts the acidic environment of gastric mucosa and helps in the colonization of H. pylori. Ammonia in conjunction with neutrophil metabolites forms carcinogenic agents that might participate in the development of gastric malignancies.
H. pylori adheres to receptors in the gastric epithelium by means of adhesins. H.pylori protein (coded by babA and babB genes) binds with human blood group antigen (Lewis b) expressed in the proximal and distal colon.
Vacuolating Cytotoxin (VacA)
The vacuolating toxin (VacA) is a major determinant of H. pylori-associated gastric disease. VacA was named for its ability to induce vacuole formation in eukaryotic cells. It is also responsible for membrane channel formation, cytochrome c release from mitochondria leading to apoptosis, and binding to cell- membrane receptors for the initiation of proinflammatory response. VacA can specifically inhibit T-cell activation and proliferation by manipulating the T-cell receptor pathway and the cell cycle.
Cytotoxin-associated gene A (CagA) & type IV secretion system (T4SS)
CagA is a bacterium derived oncoprotein which is injected into host cells via a pilus structure called type IV secretion system (T4SS). After being injected into host cells, CagA alters intracellular signal transduction pathways that facilitate the malignant transformation of gastric epithelial cells. CagA and T4SS also increase gastric inflammation (via NFκB signaling pathway) and increase IL-8 secretion which predisposes to genetic instability and carcinogenesis.
Outer Inflammatory Protein (OipA)
Outer membrane protein of H. pylori functions in adhesion and IL-8 induction. OipA has a function of inducing inflammation and actin dynamics through the phosphorylation of multiple signaling pathways that usually interact with cag PAI (CagA)-related pathways.
Duodenal Ulcer Promoting (DupA) gene
Named for its role to increase the risk of duodenal ulcer (DU). H. pylori with complete dupA cluster were associated with a 2.1-fold risk of DU than that with incomplete dupA cluster or negative dupA. DupA pathogenesis appears to involve the induction of IL-8 production in the antrum, leading to antrum-predominant gastritis, which is a well-recognized characteristic of duodenal ulcer.
References and further reading
- John C Atherton. H. pylori virulence factors. British Medical Bulletin 1998;54 (No. 1): 105-120
- Behnam Kalali et. al., H. pylori Virulence Factors: Influence on Immune System and Pathology; Mediators of Inflammation. 2014.
- William G. et.al., Virulence factors of Helicobacter pylori. International Journal of Medical Microbiology.2001; 290 (8): 647-658.
- Chang WL, Yeh YC, Sheu BS. The impacts of H. pylori virulence factors on the development of gastroduodenal diseases. J Biomed Sci. 2018;25(1):68. doi:10.1186/s12929-018-0466-9
- Roesler BM et. al., Virulence Factors of Helicobacter pylori: A Review. Clin Med Insights Gastroenterol. 2014;7:9–17. Published 2014 Mar 27. doi:10.4137/CGast.S13760