Isolated for the first time in 1982 from human gastric biopsy, Helicobacter pylori is responsible for gastritis, peptic ulcer, and gastric cancer. A pathogenicity island acquired by horizontal transfer, coding for a type IV secretion system, is a major determinant of virulence. The infection is now treated with antibiotics, and vaccines are in preparation. The geographic distribution suggests coevolution of man and Helicobacter pylori.

https://science.sciencemag.org/content/sci/284/5418/1328.full.pdf

Helicobacter pylori virulence and genetic geography.

Helicobacter pylori is a gram negative, spiral, microaerophylic bacterium that infects the stomach of more than 50% of the human population worldwide. It is mostly acquired during childhood and, if not treated, persists chronically, causing chronic gastritis, peptic ulcer disease, and in some individuals, gastric adenocarcinoma and gastric B cell lymphoma. The current therapy, based on the use of a proton-pump inhibitor and antibiotics, is efficacious but faces problems such as patient compliance, antibiotic resistance, and possible recurrence of infection. The development of an efficacious vaccine against H. pylori would thus offer several advantages. Various approaches have been followed in the development of vaccines against H. pylori, most of which have been based on the use of selected antigens known to be involved in the pathogenesis of the infection, such as urease, the vacuolating cytotoxin (VacA), the cytotoxin-associated antigen (CagA), the neutrophil-activating protein (NAP), and others, and intended to confer protection prophylactically and/or therapeutically in animal models of infection. However, very little is known of the natural history of H. pylori infection and of the kinetics of the induced immune responses. Several lines of evidence suggest that H. pylori infection is accompanied by a pronounced Th1-type CD4(+) T cell response. It appears, however, that after immunization, the antigen-specific response is predominantly polarized toward a Th2-type response, with production of cytokines that can inhibit the activation of Th1 cells and of macrophages, and the production of proinflammatory cytokines. The exact effector mechanisms of protection induced after immunization are still poorly understood. The next couple of years will be crucial for the development of vaccines against H. pylori. Several trials are foreseen in humans, and expectations are that most of the questions being asked now on the host-microbe interactions will be answered.

The Design of Vaccines Against Helicobacter Pylori and Their Development

Although colonization with any Helicobacter pylori strain is associated with peptic ulcer, it is uncertain whether the risk is greater with cagA(+) or cagA(-) strains, which differ in their biology. A nested case-control study was done, based on a cohort of 5,443 Japanese-American men examined on the Hawaiian island of Oahu from 1967 to 1970. A total of 150 men with gastric ulcer, 65 with duodenal ulcer, and 14 with both diseases were identified. The authors matched the 229 cases with 229 population controls and tested their serum for immunoglobulin G antibodies to H. pylori and immunoglobulin G antibodies to the cagA product of H. pylori using enzyme-linked immunosorbent assays. Persons with H. pylori positivity had an odds ratio of 4.0 (95% confidence interval (CI): 1.9, 8.5) for gastric ulcer and 2.5 (95% CI: 0.8, 7.4) for duodenal ulcer. For CagA positivity, the odds ratios were 1.4 (95% CI: 0.9, 2.4) for gastric ulcer and 2.6 (95% CI: 1.1, 5.8) for duodenal ulcer. Subjects who were seropositive for both H. pylori and CagA had an odds ratio of 4.4 (95% CI: 1.8, 10.5) for gastric ulcer and 5.8 (95% CI: 1.1, 30.0) for duodenal ulcer. The results suggest that colonization with a cag(+) H. pylori strain elevates the risk beyond that of a cag(-) H. pylori strain for both gastric and duodenal ulcers.

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Relation between Helicobacter pylori cagA Status and Risk of Peptic Ulcer Disease

Secretion of proteins by Helicobacter pylori may contribute to gastric inflammation and epithelial damage. An in vitro analysis was designed to identify proteins released by mechanisms other than nonspecific lysis. The radioactivity of proteins in the supernatant was compared with that of the intact organism by two-dimensional gel phosphorimaging following a 4-h pulse-chase. The ratio of the amount of UreB, a known cytoplasmic protein, in the supernatant to that in the pellet was found to be 0.25, and this was taken as an index of lysis during the experiments (n = 6). Ratios greater than that of UreB were used to distinguish proteins that were selectively released into the medium. Thus, proteins enriched more than 10-fold in the supernatant compared to UreB were identified by mass spectrometry. Sixteen such proteins were present in the supernatant: VacA; a conserved secreted protein (HP1286); putative peptidyl cis-trans isomerase (HP0175); six proteins encoded by HP0305, HP0231, HP0973, HP0721, HP0129, and HP0902; thioredoxin (HP1458); single-stranded-DNA-binding 12RNP2 precursor (HP0827); histone-like DNA-binding protein HU (HP0835); ribosomal protein L11 (HP1202); a putative outer membrane protein (HP1564); and outer membrane proteins Omp21 (HP0913) and Omp20 (HP0912). All except HP0902, thioredoxin, HP0827, HP0835, and HP1202 had a signal peptide. When nalidixic acid, a DNA synthesis inhibitor, was added to inhibit cell division but not protein synthesis, to decrease possible contamination due to outer membrane shedding, two outer membrane proteins (Omp21 and Omp20) disappeared from the supernatant, and the amount of VacA also decreased. Thus, 13 proteins were still enriched greater than 10-fold in the medium after nalidixic acid treatment, suggesting these were released specifically, possibly by secretion. These proteins may be implicated in H. pylori-induced effects on the gastric epithelium.

Proteins Released by Helicobacter pylori In Vitro

BACKGROUND Studies in Western populations suggest that cagA, iceA, and vacA gene status in Helicobacter pylori isolates is associated with increased virulence and peptic ulcer disease. AIM To investigate the relationship between peptic ulcer and expression of Lewis (Le) antigens as well as cagA, iceA, and vacA in H pylori isolates in Singapore. METHODS Expression of Le antigens in H pylori isolates obtained from patients with dyspepsia was measured by enzyme linked immunosorbent assay. The cagA, iceA, and vacA status was determined by polymerase chain reaction. RESULTS Of 108 H pylori isolates, 103 (95.4%) expressed Le x and/or Le y , while Le a and Le b were expressed in 23 (21.3%) and 47 (43.5%) isolates, respectively. Expression of two or more Le antigens (Le x , Le y , Le a , or Le b ) was significantly higher in H pylori isolated from ulcer patients than in non-ulcer patients (89.6% v 73.2%, p=0.035). There were no significant differences in the prevalence of cagA or iceA 1 in H pylori isolates from peptic ulcer and non-ulcer patients (86.6% v 90.2% for cagA ; 70.1% v 68.3% for iceA 1), and no association of peptic ulcer with any specific vacA genotype. CONCLUSIONS The present study indicates that peptic ulcer disease is associated with increased expression of Lewis antigens but not cagA, iceA, or vacA genotype in H pylori isolates in our population. This suggests that cagA, iceA, and vacA are not universal virulence markers, and that host-pathogen interactions are important in determining clinical outcome.

https://gut.bmj.com/content/gutjnl/47/1/18.full.pdf

Association of peptic ulcer with increased expression of Lewis antigens but not cagA, iceA, and vacA in Helicobacter pylori isolates in an Asian population

Background: Helicobacter pylori strains possessing the cagA gene have been postulated to have a disease-specific relationship to peptic ulcer. The purpose of this study was to investigate the relationship between the infection with Helicobacter pylori expressing the cagA gene and the development of peptic ulcer diseases in Korean patients. Methods: Genomic DNA and bacterial mRNA in the gastric mucosa were amplified by polymerase chain reaction (PCR) and reverse transcription PCR, using synthetic oligonucleotide primers to cagA genes to compare the prevalence of cagA genes in 35 patients with non-ulcer gastritis and 99 patients with gastric or duodenal ulcer disease (53 and 46, respectively). Two different primer sets for the cagA gene were used. The first primer set amplified a 298-bp region (nucleotides 1751-2048), and the second set amplified a 349-bp region (nucleotides 1228-1249). Results: The expected 298- and 349-bp PCR amplicons were identified as follows: 1) 32 (91.4%) and 30 (85.7%) of 35 non-ulc...

Infection with Helicobacter pylori Expressing the cagA Gene Is Not Associated with an Increased Risk of Developing Peptic Ulcer Diseases in Korean Patients

J. G. Kim

Papers

Infection with Helicobacter pylori Expressing the cagA Gene Is Not Associated with an Increased Risk of Developing Peptic Ulcer Diseases in Korean Patients