Helicobacter pylori is a gram-negative bacterium that affects the human gastric mucosa. The bacterium is a contributor to the pathogenicity of several diseases including chronic gastritis, peptic ulcers, gastric adenocarcinomas, and gastric mucosa–associated lymphoid tissue lymphomas (3, 5). Gastric cancer still remains a concern in Asian countries, yet the incidence varies greatly amongst the different regions of Asia. Japan, Korea, and China are considered as high-risk areas, whereas Vietnam and Thailand are considered as intermediate-risk and low-risk, respectively. In Asian countries, the prevalence of gastric cancer is higher amongst the elderly population (8).
While approximately 50 percent of the world’s population may be infected with H. pylori, infection rates are generally higher in developing countries, with the majority of infections occurring during childhood, the period of highest risk. There is, however, usually a long latency period with disease manifestations appearing later in adulthood. The prevalence of H. pylori infections is variable depending on age, race, geographic area, socioeconomic status and ethnicity (3).
Recent molecular epidemiologic data suggest that this variation is likely due to the genetic diversity of H. pylori. All patients that are infected with H. pylori will develop gastritis, while there is also the possibility of ulcer disease and an increased risk to gastric cancer. As there is such great variation, many studies sought to identify the different factors that determine the disease outcome of infection. Thus far, the major virulence factors that contribute to either gastritis or gastric cancer include the cagA (cytotoxin-associated gene) and vacA (vacuolating toxin) genes, which also vary between strains different regions of the world. For instance, the 3’ repeat region of the cagA gene varies between strains from Western countries and those from East Asian countries. Furthermore, there is variation in the vacA gene structure in both the signal region, designated as s1 and s2 and the middle region, designated as m1 and m2. The most virulent genotypes amongst countries with high gastric cancer incidence rates are vacA s1/m1 and the East Asian type cagA (8)
H. pylori can be classified into two classes, type I and type II, based on the presence or absence of the cag pathogenicity island (4). The cag pathogenicity island is a 40 kilobase segment of DNA, consisting of 31 genes, in which the majority of them encode a type IV secretion system (T4SSs). The T4SSs are found in many Gram-negative bacteria and are ancestrally related to conjugation systems. T4SSs are functionally diverse although they generally consist of 11 VirB proteins and a coupling protein, VirD4. Currently, the role of the T4SS-specific accessory factors is unknown except for CagF and Cag L. CagF is a chaperone-like protein and is crucial for translocating CagA. The H. pylori T4SSs form a pilus for the injection of virulence factors. This is mediated by CagL, a pilus-covering protein, which acts as an adhesin to connect the T4SS with the target cells (1). Following the interaction of CagL with integrin receptors, the type IV secretion system acts as a molecular syringe and is responsible for translocating the CagA protein into gastric epithelial cells to be tyrosine phosphorylated by Src kinases (6, 9).
Phosphorylated CagA will then interact with SH2 domain-containing host cell proteins such as the tyrosine phosphatase SHP-2 and the adaptor protein CRK. The interactions of CagA with signaling molecules subsequently lead to a rearrangement of the cytoskeleton and cell elongation, referred to as a “hummingbird” morphological chance. Thus, the alteration of the host cell architecture by CagA may be a potential cause of virulence (7). The hummingbird phenotype occurs due to Cag-activated SHP-2 dephosphorylation of the focal adhesion kinase, which promotes the activation of ERK MAP kinases. Activated MAP kinases are important in cell cycle progression, which is thought to contribute to gastric cancer promotion (9).
CagA is also able to perturb cell functions through tyrosine phosphorylation-independent mechanisms. Non-phosphorylated CagA interacts with host cell proteins such as the epithelial tight junction-scaffolding protein zonulin, the cell adhesion protein E-cadherin, and other adaptor proteins. This leads to the disruption of tight and adherent junctions and induces pro-inflammatory and mitogenic responses that may be important in promoting gastric cancer (9). In vivo studies have shown that H. pylori infections are related to the release of pro-inflammatory cytokines and chemokines such as IL-8. Induction of IL-8 appears to be dependent on the cag pathogenicity island. (9).
In addition to binding to SHP-2, CagA also interacts with the C terminal Src kinase (Csk), which phosphorylates src family kinases (SFKs) and inhibits their activity. Since SFKS are responsible for CagA tyrosine phosphorylation, this indicates that there is a feedback regulatory mechanism that dampens the phosphorylation-dependent activites of CagA. This also means that the presence of a negative feedback loop may ensure that there is a balance between cagA-posiive H.pylori and the human stomach without the bacterium causing acute and fatal mucosal damage to the host (2).
Another important virulent determinant of H. pylori infections is the vacuolating cytotoxin, VacA. VacA is a secreted exotoxin that inserts itself into the epithelial cell membrane and forms an anion selective, voltage-dependent channel (7). The toxin also facilitates the formation of transmembrane pores, which increases the permeability of the gastric epithelium. Together, these mechanisms may provide nutrients for the bacterium (4).
VacA is responsible for structurally altering epithelial cells, disrupting endosomal maturation, induces mitochondrial damage, cytochrome c release and apoptosis of gastric epithelial cells. Some studies have also suggested that VacA has multiple effects on the immune system by interfering with phagocytosis and antigen presentation. Furthermore, VacA inhibits the activation of NFAT, which is required for genes that are involved in T cell activation. Because of the dampened immune response, it is believed that H. pylori is able to evade the adaptive immune response and cause a persistent infection. The majority of these effects, however, have only been observed in vitro. It remains to be established whether the same clinical effects would be observed in vivo in humans (9).
H. pylori is able to persist in the host due to a variety of mechanisms, including preventing its own toxicity through negative feedback loops or through the suppression of the immune system. While the mechanisms for cagA as a virulence factor are becoming more evident, further research will be required to define additional molecular mechanisms.
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