Kathleen R. Jones

Polymorphism in the CagA EPIYA Motif Impacts Development of Gastric Cancer

ABSTRACT Helicobacter pylori causes diseases ranging from gastritis to peptic ulcer disease to gastric cancer. Geographically, areas with high incidences of H. pylori infection often overlap with areas with high incidences of gastric cancer, which remains one of the leading causes of cancer-related deaths worldwide. Strains of H. pylori that carry the virulence factor cytotoxin-associated gene A (cagA) are much more likely to be associated with the development of gastric cancer. Moreover, particular C-terminal polymorphisms in CagA vary by geography and have been suggested to influence disease development. We conducted a large-scale molecular epidemiologic analysis of South Korean strains and herein report a statistical link between the East Asian CagA EPIYA-ABD genotype and the development of gastric cancer. Characterization of a subset of the Korean isolates showed that all strains from cancer patients expressed and delivered phosphorylatable CagA to host cells, whereas the presence of the cagA gene did not strictly correlate to expression and delivery of CagA in all noncancer strains.

A Tale of Two Toxins: Helicobacter Pylori CagA and VacA Modulate Host Pathways that Impact Disease

Helicobacter pylori is a pathogenic bacterium that colonizes more than 50% of the worlds population, which leads to a tremendous medical burden. H. pylori infection is associated with such varied diseases as gastritis, peptic ulcers, and two forms of gastric cancer: gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. This association represents a novel paradigm for cancer development; H. pylori is currently the only bacterium to be recognized as a carcinogen. Therefore, a significant amount of research has been conducted to identify the bacterial factors and the deregulated host cell pathways that are responsible for the progression to more severe disease states. Two of the virulence factors that have been implicated in this process are cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA), which are cytotoxins that are injected and secreted by H. pylori, respectively. Both of these virulence factors are polymorphic and affect a multitude of host cellular pathways. These combined facts could easily contribute to differences in disease severity across the population as various CagA and VacA alleles differentially target some pathways. Herein we highlight the diverse types of cellular pathways and processes targeted by these important toxins.

Epidemiological Link between Gastric Disease and Polymorphisms in VacA and CagA

ABSTRACT Gastritis, peptic ulcer disease, and gastric cancer are a few of the diverse disease manifestations that have been shown to be associated with infection by Helicobacter pylori. Why some individuals develop more severe forms of disease remains largely unknown. In this study, 225 South Korean strains were genotyped for vacA and then analyzed to determine if particular genotypes varied across disease state, sex, or cagA allele. Of these strains, 206 strains carried an s1/i1/m1 allele, 11 strains carried an s1/i1/m2 allele, and 8 strains carried an s1/i2/m2 allele. By using Fishers exact test, a statistical association between variations in the cagA and vacA alleles was identified (P = 0.0007), and by using log linear modeling, this variation was shown to affect the severity of disease outcome (P = 0.027). Additionally, we present evidence that variation within the middle region of VacA contributes significantly to the distribution of vacA alleles across gender (P = 0.008) as well as the association with disease outcome (P = 0.011). In this South Korean population, the majority of H. pylori strains carry the vacA s1/i1/m1 allele and the CagA EPIYA-ABD allele. These facts may contribute to the high incidence of gastric maladies, including gastric cancer.

Sodium Chloride Affects Helicobacter pylori Growth and Gene Expression

Epidemiological evidence links high-salt diets and Helicobacter pylori infection with increased risk of developing gastric maladies. The mechanism by which elevated sodium chloride content causes these manifestations is unclear. Here we characterize the response of H. pylori to temporal changes in sodium chloride concentration and show that growth, cell morphology, survival, and virulence factor expression are all altered by increased salt concentration.

Polymorphisms in the Intermediate Region of VacA Impact Helicobacter pylori-Induced Disease Development

ABSTRACT Helicobacter pylori is the etiological agent of diseases such as gastritis, gastric and duodenal ulcers, and two types of gastric cancers. While some insight has been gained into the etiology of these diverse manifestations, by and large, the reason that some individuals develop more severe disease remains elusive. Recent studies have focused on the roles of H. pylori toxins CagA and VacA on the disease process and have suggested that both toxins are intimately involved. Moreover, CagA and VacA are polymorphic within different H. pylori strains, and particular polymorphisms seem to show a correlation with the development of particular disease states. Among VacA polymorphisms, the intermediate region has recently been proposed to play a major role in disease outcome. In this article, we describe a detailed sequence analysis of the polymorphic intermediate region of vacA from strains obtained from a large South Korean population. We show that polymorphisms found at amino acid position 196 are associated with more severe disease manifestations. Additionally, polymorphisms found at amino acid position 231 are linked to disease in strains that carry the non-EPIYA-ABD allele of CagA. Collectively, these data help explain the impact of the VacA intermediate region on disease and lead to the hypothesis that there are allele-driven interactions between VacA and CagA.

Helicobacter pylori homB, but not cagA, is Associated with Gastric Cancer in Iran

ABSTRACT While several distinct virulence factors of Helicobacter pylori have been shown to be associated with different clinical outcomes, there is still much to learn about the role of different bacterial factors in gastric carcinogenesis. This study looked at the distribution of the cagA, homA, and homB genes in strains isolated from patients suffering from gastroduodenal diseases in Iran and assessed if there was any association between disease state and the presence of the aforementioned virulence factors. Genomic DNA from 138 H. pylori strains was isolated and genotyped via PCR. Strains were obtained from dyspeptic patients (35 from gastritis patients, 62 from peptic ulcer patients, and 41 from gastric cancer patients) at the Teaching Touba Clinic and Imam Hospital of the Mazandaran University of Medical Sciences in Sari, Iran. The overall prevalence rates of cagA, homA, and homB were 58%, 54%, and 43%, respectively. Stratification of patients showed a significant difference in the prevalence of H. pylori virulence genes across the disease states. The frequency of homB was statistically significantly higher in gastric cancer patients (78%) than in patients suffering from peptic ulcers (20%) or gastritis (43%) (P < 0.0001). The presence of homB was also associated with the presence of cagA (r = 0.243). These data suggest that in this population the presence of homB may be a predictor of more virulent strains of H. pylori and influence the severity of disease manifestation.

Who's Winning the War? Molecular Mechanisms of Antibiotic Resistance in Helicobacter pylori.

The ability of clinicians to wage an effective war against many bacterial infections is increasingly being hampered by skyrocketing rates of antibiotic resistance. Indeed, antibiotic resistance is a significant problem for treatment of diseases caused by virtually all known infectious bacteria. The gastric pathogen Helicobacter pylori is no exception to this rule. With more than 50% of the worlds population infected, H. pylori exacts a tremendous medical burden and represents an interesting paradigm for cancer development; it is the only bacterium that is currently recognized as a carcinogen. It is now firmly established that H. pylori infection is associated with diseases such as gastritis, peptic and duodenal ulceration and two forms of gastric cancer, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. With such a large percentage of the population infected, increasing rates of antibiotic resistance are particularly vexing for a treatment regime that is already fairly complicated; treatment consists of two antibiotics and a proton pump inhibitor. To date, resistance has been found to all primary and secondary lines of antibiotic treatment as well as to drugs used for rescue therapy.

The Geographic Origin of Helicobacter pylori Influences the Association of the homB gene with Gastric Cancer

ABSTRACT We found that South Korean Helicobacter pylori isolates predominantly carry homB at locus B and that there is no association between the homB allele and the cagA allele or the development of gastric cancer within this population. Uniquely, several East Asian strains carried multiple copies of the hom genes.