The Helicobacter pylori infection of the human gastric mucosa causes chronic active gastritis and peptic ulcers and is associated with the development of gastric cancer. Epidemiological studies show that these gastric diseases are related to virulent H. pylori strains that harbor the cytotoxin‐associated gene pathogenicity island (cag PAI). The cag PAI is a DNA insertion in the H. pylori chromosome that encodes ~ 27 proteins, including the oncoprotein CagA. Approximately 20 of these proteins have been designated as cag type IV secretion system (T4SS) components. However, only 11 of these proteins share function, structure, and/or sequence similarities with the prototypical VirB/VirD4 T4SS of Agrobacterium tumefaciens. The VirB/VirD4 orthologs of the cag T4SS of H. pylori are required for CagA translocation and stimulate the gastric epithelial cells to produce and secrete interleukin‐8 (IL‐8). The cag PAI encodes eight additional proteins, such as Cag3 (Cagδ/HP0522), CagM (Cag16/HP0537), CagU (Cag11/HP0531), CagI (Cag19/HP0540), and CagH (Cag20/HP0541), which are also required for the translocation of CagA and IL‐8 secretion, meanwhile CagF (Cag22/HP0543), CagG (Cag21/HP0542), and CagZ (Cag6/HP0526) are just required for the translocation of CagA. However, relatively little is known about their functions and structural organization because they exhibit a nondetectable sequence similarity with T4SS components in the current databases. In this review, we conducted an exhaustive analysis of the literature to present the biochemistry, putative role, localization, and interactions of each of these eight additional cag T4SS components.

ResumenLa infección por Helicobacter pylori incrementa el riesgo de un amplio espectro de cuadros clínicos, que van de la úlcera péptica al cáncer gástrico. Sin embargo, la infección sólo induce ulceración gástrica y duodenal o cáncer gástrico en la minoría de los sujetos infectados debido que las cepas de H. pylori son genéticamente diversas y expresan diferentes factores de virulencia. Así, los individuos infectados por cepas que expresan estos factores de virulencia probablemente desarrollan enfermedades severas como el cáncer gástrico. Sin embargo, la ancestral relación entre H. pylori y los humanos sugiere que algunas cepas pueden ser beneficiosas para la salud humana. Por lo tanto, la administración generalizada de tratamientos con antibiótico podría eventualmente causar problemas. El desarrollo de vacunas con base en factores de virulencia que confieran protección a largo plazo es la mejor estrategia para el control y/o eliminación de cepas patógenas. Los diferentes esquemas y formulaciones de inmunización diseñados para evaluar las vacunas con base en factores de virulencia en modelos animales han dado resultados prometedores. Sin embargo, ha sido necesario probar si estos resultados pueden ser reproducidos en humanos. Este trabajo revisa los recientes estudios de vacunación que han explorado esta posibilidad: vacunas orales usando ureasa o células completas-inactivadas con LT como adyuvante y ureasa expresada en vectores de Salmonella spp.; además de una vacuna intramuscular multicomponente con hidróxido de aluminio como adyuvante. Aunque estos estudios han logrado limitado éxito han establecido las bases para el desarrollo de una vacuna eficaz contra esta infección. AbstractHelicobacter pylori infection increases the risk for a wide spectrum of clinical outcomes, ranging from peptic ulcer disease to gastric cancer. However, the infection induces gastric and duodenal ulceration or gastric cancer in only a minority of infected subjects because H. pylori strains are genetically diverse and express different virulence factors. Individuals infected with strains that express these virulence factors probably develop severe diseases such as gastric cancer. Nevertheless, the ancient relationship between H. pylori and humans suggests that some strains could be beneficial to human health, which means that generalized administration of antibiotic therapy could eventually cause problems. The development of vaccines based on virulence factors that provide long-term protection is the best strategy for control and/or elimination of pathogenic strains. The different immunization schemes and formulations designed to evaluate the vaccines based on virulence factors in animal models have offered promising results. However, it is necessary to determine whether or not these results can be reproduced in humans. This article reviews recent vaccination studies that explore this possibility: oral vaccines using urease or inactivated whole cells plus LT as adjuvant and urease expressed in Salmonella spp. vectors, as well as a p...

Helicobacter pylori is associated with the development of several lesions in the human stomach. This chronic infection produces gastritis, which can progress to intestinal metaplasia and gastric cancer. To date, there is very little information regarding gene-expression in the different phases of progression caused by chronic H. pylori infection. In this study, we performed a genome-wide gene-expression analysis in gastric biopsies of patients chronically infected with H. pylori, using the potential of high-throughput technologies that have not been fully exploited in this area. Here we illustrate the potential correlation of H. pylori infection with the gene expression changes in follicular gastritis, chronic gastritis and intestinal metaplasia. We also suggest its potential as biomarkers of each condition. An exploratory set of 21 biopsies from patients with follicular gastritis, chronic gastritis, and intestinal metaplasia were analyzed by gene-expression microarrays in order to identify the biological processes altered in each lesion. The microarray data was corroborated by real-time PCR, while 79 Formalin-Fixed Paraffin-Embeded samples were analyzed by immunohistochemistry. Follicular gastritis exhibited significant enrichment in genes associated with glutamate signaling, while chronic gastritis showed a down-regulation in metallothionein 1 and 2 and in oxidative phosphorylation-related genes, which could be associated with the chronic infecton of H. pylori. Intestinal metaplasia exhibited an over-expression of gastrointestinal stem cell markers, such asLGR5 and PROM1, as well as messenger RNA and nucleic acid metabolism-related genes. The gene-expression patterns found in this study provide new comparative information about chronic gastritis, follicular gastritis and intestinal metaplasia that may play an important role in the development of gastric cancer.

BackgroundHelicobacter pylori is associated with chronic gastritis, peptic ulcers, and gastric cancer. Two major virulence factors of H. pylori have been described: the pathogenicity island cag (cag PAI) and the vacuolating cytotoxin gene (vacA). Virtually all strains have a copy of vacA, but its genotype varies. The cag PAI is a region of 32 genes in which the insertion of IS605 elements in its middle region has been associated with partial or total deletions of it that have generated strains with varying virulence. Accordingly, the aim of this work was to determine the cag PAI integrity, vacA genotype and IS605 status in groups of isolates from Mexican patients with non-peptic ulcers (NPU), non-bleeding peptic ulcers (NBPU), and bleeding peptic ulcers (BPU).MethodsThe cag PAI integrity was performed by detection of eleven targeted genes along this locus using dot blot hybridization and PCR assays. The vacA allelic, cag PAI genotype 1 and IS605 status were determined by PCR analysis.ResultsGroups of 16-17 isolates (n = 50) from two patients with NPU, NBPU, and BPU, respectively, were studied. 90% (45/50) of the isolates harbored a complete cag PAI. Three BPU isolates lacked the cag PAI, and two of the NBPU had an incomplete cag PAI: the first isolate was negative for three of its genes, including deletion of the cagA gene, whereas the second did not have the cagM gene. Most of the strains (76%) had the vacA s1b/m1 genotype; meanwhile the IS605 was not present within the cag PAI of any strain but was detected elsewhere in the genome of 8% (4/50).ConclusionThe patients had highly virulent strains since the most of them possessed a complete cag PAI and had a vacA s1b/m1 genotype. All the isolates presented the cag PAI without any IS605 insertion (genotype 1). Combined vacA genotypes showed that 1 NPU, 2 NBPU, and 1 BPU patients (66.6%) had a mixed infection; coexistence of H. pylori strains with different cag PAI status was observed in 1 NBPU and 2 BPU (50%) of the patients, but only two of these patients (NBPU and BPU) had different vacA genotypes.

Helicobacter pylori infects more than half of the world's population, making it the most widespread infection of bacteria. It has high genetic diversity and has been considered as one of the most variable bacterial species. In the present study, a PCR-based method was used to detect the presence and the relative frequency of homologous recombination between repeat sequences (>500 bp) in H. pylori 26695. All the recombinant structures have been confirmed by sequencing. The inversion generated between inverted repeats showed distinct features from the recombination for duplication or deletion between direct repeats. Meanwhile, we gave the mathematic reasoning of a general formula for the calculation of relative recombination frequency and indicated the conditions for its application. This formula could be extensively applied to detect the frequency of homologous recombination, site-specific recombination, and other types of predictable recombination. Our results should be helpful for better understanding the genome evolution and adaptation of bacteria.