Search Results (14)

Helicobacter pylori possesses an unusually high number of restriction–modification (R-M) systems relative to its small genome, contributing to a methylome increasingly implicated in bacterial gene regulation. In this study, we analyzed the methylomes of two mutant strains of H. pylori 26695: ∆rdxA (control) and ∆rdxA/∆arsS. Each mutant was cultivated under neutral (pH 7) and acidic (pH 5) growth conditions. We identified one conspicuous hypomethylated region of 21 kBp possessing 21 annotated genes across each methylome. Notably, over 600 protein coding regions and 10 different promoters displayed differential methylation between pH conditions, including several virulence factors. The vacA gene, encoding the Vacuolating Cytotoxin A, exhibited eight differentially methylated positions between pH 7 and pH 5 within the H. pylori 26695 control mutant methylome, potentially contributing to its previously documented 32-fold down regulation of mRNA in acidic environments. pH-dependent methylation changes were widespread within the cag pathogenicity island, genes encoding cell envelope proteins including adhesin-encoding sabA, babA, and hopQ, and numerous flagellar-associated genes. These results reveal the plasticity of the H. pylori methylome and suggest that DNA methylation is responsive to environmental pH in both ArsRS-dependent and independent manners. Methylome dynamics may serve as an important layer of gene regulation in acclimation to hostile gastric environments and promote persistent infection. Full article

Helicobacter pylori (H. pylori) is a highly adaptable gastric pathogen with marked genomic plasticity. Whilst functional CRISPR-Cas systems provide adaptive immunity in many bacteria, they have not been identified in H. pylori, unlike CRISPR-like sequences. In this study, eight H. pylori genomes were analysed using the bioinformatics tools CRISPRCasFinder, CRISPRCasTyper, and CRISPRloci. A total of 25 CRISPR-like arrays were identified, showing high conservation (88%) both between and within strains, suggesting that these arrays are not random remnants but rather organised structures possibly involved in cellular processes. Notably, a structural association was observed between the CRISPR-like sequences and the cag pathogenicity island (CagA-PAI). Conversely, CagA-PAI instability in specific strains was observed in the presence of the TnpA and TnpB transposons. Furthermore, in strain 29CaP, CRISPR-like assemblies were located in genomic proximity to the prophage Helico 1961P, leading to the hypothesis of a compensatory or regulatory effect in the absence of CagA-PAI. Taken together, these findings indicate that CRISPR-like arrays in H. pylori characterise a genomic architecture within regions of high plasticity. This study provides a solid exploratory foundation for future functional research on the adaptive and pathogenic evolution of H. pylori. Full article

Helicobacter pylori infects at least half the population worldwide, and its highly diverse genomic content correlates with its geographic distribution because of its prolonged relationship with humans. The extremely low infection prevalence alongside low inflammation severity observed in some countries might be caused by strains with low virulence potential. Therefore, this study aimed to investigate whole-genome analysis datasets of Sri Lankan H. pylori strains. H. pylori strains were isolated from biopsy specimens and underwent whole-genome sequencing to investigate their antibiotic resistance and virulence potential. The prevalence of H. pylori infection in Sri Lanka is extremely low (1.7% in a previous study), and only six H. pylori strains were successfully isolated from bacterial culture. Antibiotic resistance analysis showed a high prevalence of metronidazole resistance (83.3%, five out of six strains), and investigation of the related genes showed truncation of the rdxA and frxA genes and single-nucleotide polymorphisms in the rdxA, frxA, ribF, omp11, and fur genes. Most virulence genes of the 144 assessed were present, except for the cag pathogenicity island (cagPAI) (absent in four out of six strains), babA/B/C, and tlpB genes. An incomplete type 4 secretion system (tfs) was found in three strains. A pan-genome analysis with non-Sri Lankan H. pylori strains showed that the htpX gene was found only in Sri Lankan strains (p-corrected = 0.0008). A phylogenetic analysis showed that the Sri Lankan strains clustered with strains from hpAsia2 and hpEurope. This comparative genomic study shows that H. pylori strains with low virulence potential are present in countries with a low prevalence of infection and disease severity, indicating a strain-type geographical pattern. The tailored guidelines for screening and treatment strategy for each region are necessary to obtain effective and efficient eradication. Full article

Background: The prevalence of gastric cancer in Mongolia, in East Asia, remains the highest in the world. However, most Helicobacter pylori strains in Mongolia have a less virulent Western-type CagA. We aimed to determine how H. pylori genomic variation affected gastric diseases, especially gastric cancer, based on comprehensive genome analysis. Methods: We identified a set of 274 virulence-associated genes in H. pylori, including virulence factor and outer membrane protein (OMP) genes, the type four secretion system gene cluster, and 13 well-known virulence gene genotypes in 223 H. pylori strains and their associations with gastric cancer and other gastric diseases. We conducted a genome-wide association study on 158 H. pylori strains (15 gastric cancer and 143 non-gastric cancer strains). Results: Out of 274 genes, we found 13 genes were variable depending on disease outcome, especially iron regulating OMP genes. H. pylori strains from Mongolia were divided into two main subgroups: subgroup (Sg1) with high risk and Sg2 with low risk for gastric cancer. The general characteristics of Sg1 strains are that they possess more virulence genotype genes. We found nine non-synonymous single nucleotide polymorphisms in seven genes that are linked with gastric cancer strains. Conclusions: Highly virulent H. pylori strains may adapt through host-influenced genomic variations, potentially impacting gastric carcinogenesis. Full article

Gastric cancer is a challenging public health concern worldwide and remains a leading cause of cancer-related mortality. The primary risk factor implicated in gastric cancer development is infection with Helicobacter pylori. H. pylori induces chronic inflammation affecting the gastric epithelium, which can lead to DNA damage and the promotion of precancerous lesions. Disease manifestations associated with H. pylori are attributed to virulence factors with multiple activities, and its capacity to subvert host immunity. One of the most significant H. pylori virulence determinants is the cagPAI gene cluster, which encodes a type IV secretion system and the CagA toxin. This secretion system allows H. pylori to inject the CagA oncoprotein into host cells, causing multiple cellular perturbations. Despite the high prevalence of H. pylori infection, only a small percentage of affected individuals develop significant clinical outcomes, while most remain asymptomatic. Therefore, understanding how H. pylori triggers carcinogenesis and its immune evasion mechanisms is critical in preventing gastric cancer and mitigating the burden of this life-threatening disease. This review aims to provide an overview of our current understanding of H. pylori infection, its association with gastric cancer and other gastric diseases, and how it subverts the host immune system to establish persistent infection. Full article

(1) Background: Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide. Helicobacter pylori infection is a major risk factor, but other microbial species may also be involved. In the context of an earlier proteomics study of serum and biopsies of patients with gastroduodenal diseases, we explored here a simplified microbiome in these biopsies (H. pylori, Acinetobacter baumannii, Escherichia coli, Fusobacterium nucleatum, Bacteroides fragilis) on the protein level. (2) Methods: A cohort of 75 patients was divided into groups with respect to the findings of the normal gastric mucosa (NGM) and gastroduodenal disorders such as gastritis, ulcer, and gastric cancer (GC). The H. pylori infection status was determined. The protein expression analysis of the biopsy samples was carried out using high-definition mass spectrometry of the tryptic digest (label-free data-independent quantification and statistical analysis). (3) Results: The total of 304 bacterial protein matches were detected based on two or more peptide hits. Significantly regulated microbial proteins like virulence factor type IV secretion system protein CagE from H. pylori were found with more abundance in gastritis than in GC or NGM. This finding could reflect the increased microbial involvement in mucosa inflammation in line with current hypotheses. Abundant proteins across species were heat shock proteins and elongation factors. (4) Conclusions: Next to the bulk of human proteins, a number of species-specific bacterial proteins were detected in stomach biopsies of patients with gastroduodenal diseases, some of which, like those expressed by the cag pathogenicity island, may provide gateways to disease prevention without antibacterial intervention in order to reduce antibiotic resistance. Full article

Gastric cancer (GC) is the fifth leading cause of cancer deaths in the world, with variations across geographical regions and ethnicities. Emerging evidence indicates that miRNA expression is dysregulated in GC and its polymorphisms may contribute to these variations, which has yet to be explored in Latin American populations. In a case-control study of 310 GC patients and 311 healthy donors from Chile, we assessed the association of 279 polymorphisms in 242 miRNA genes. Two novel polymorphisms were found to be associated with GC: rs4822739:C>G (miR-548j) and rs701213:T>C (miR-4427). Additionally, rs1553867776:T>TCCCCA (miR-4274) and rs12416605:C>T (miR-938) were associated with intestinal-type GC, and rs4822739:C>G (miR-548j) and rs1439619:T>G (miR-3175) with TNM I-II stage. The polymorphisms rs6149511:T> TGAAGGGCTCCA (miR-6891), rs404337:G>A (miR-8084), and rs1439619:T>G (miR-3175) were identified among H.pylori-infected GC patients and rs7500280:T>C (miR-4719) and rs1439619:T>G (miR-3175) were found among H. pylori cagPAI+ infected GC cases. Prediction analysis suggests that seven polymorphisms could alter the secondary structure of the miRNA, and the other one is located in the seed region of miR-938. Targets of miRNAs are enriched in GC pathways, suggesting a possible biological effect. In this study, we identified seven novel associations and replicated one previously described in Caucasian population. These findings contribute to the understanding of miRNA genetic polymorphisms in the GC pathogenesis. Full article

Helicobacter pylori causes persistent infection in the gastric epithelium of more than half of the world’s population, leading to the development of severe complications such as peptic ulcer diseases, gastric cancer, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Several virulence factors, including cytotoxin-associated gene A (CagA), which is translocated into the gastric epithelium via the type 4 secretory system (T4SS), have been indicated to play a vital role in disease development. Although infection with strains harboring the East Asian type of CagA possessing the EPIYA-A, -B, and -D sequences has been found to potentiate cell proliferation and disease pathogenicity, the exact mechanism of CagA involvement in disease severity still remains to be elucidated. Therefore, we discuss the possible role of CagA in gastric pathogenicity. Full article

Helicobacter pylori (H. pylori) represents an independent risk factor for Gastric Cancer (GC). First Degree Relatives (FDR) of GC subjects and Autoimmune Gastritis (AG) patients are both at increased risk for GC. H. pylori genetic heterogeneity within the gastric niche of FDR and AG individuals has been little explored. To understand whether they exploit an increased H. pylori stability and virulence, 14 AG, 25 FDR, 39 GC and 13 dyspeptic patients (D) were investigated by a cultural PCR-based approach characterizing single colonies-forming-units. We chose three loci within the Cytotoxin-associated gene-A Pathogenicity Island (CagPAI) (cagA,cagE,virB11), vacA, homA and homB as markers of virulence with reported association to GC. Inflammatory/precancerous lesions were staged according to Sydney System. When compared to D, FDR, similarly to GC patients, were associated to higher atrophy (OR = 6.29; 95% CI:1.23–31.96 in FDR; OR = 7.50; 95% CI:1.67–33.72 in GC) and a lower frequency of mixed infections (OR = 0.16; 95% CI:0.03–0.81 in FDR; OR = 0.10; 95% CI:0.02–0.48 in GC). FDR presented also an increased neutrophil infiltration (OR = 7.19; 95% CI:1.16–44.65). Both FDR and GC carried a higher proportion of CagPAI⁺vacAs1i1mx⁺homB⁺ profiles (OR = 2.71; 95% CI: 1.66–4.41 and OR = 3.43; 95% CI: 2.16–5.44, respectively). Conversely, AG patients presented a lower frequency of subtypes carrying a stable CagPAI and vacAs1i1mx. These results underline different H. pylori plasticity in FDR and AG individuals, and thus, a different host-bacterium interaction capacity that should be considered in the context of eradication therapies. Full article

Gastric cancer is a major health burden and is the fifth most common malignancy and the third most common cause of death from cancer worldwide. Development of gastric cancer involves several aspects, including host genetics, environmental factors, and Helicobacter pylori infection. There is increasing evidence from epidemiological studies of the association of H. pylori infection and specific virulence factors with gastric cancer. Studies in animal models indicate H. pylori is a primary factor in the development of gastric cancer. One major virulence factor in H. pylori is the cytotoxin-associated gene A (cagA), which encodes the CagA protein in the cag pathogenicity island (cag PAI). Meta-analysis of studies investigating CagA seropositivity irrespective of H. pylori status identified that CagA seropositivity increases the risk of gastric cancer (OR = 2.87, 95% CI: 1.95–4.22) relative to the risk of H. pylori infection alone (OR = 2.31, 95% CI: 1.58–3.39). Eradicating H. pylori is a strategy for reducing gastric cancer incidence. A meta-analysis of six randomised controlled trials (RCTs) suggests that searching for and eradicating H. pylori infection reduces the subsequent incidence of gastric cancer with a pooled relative risk of 0.66 (95% CI: 0.46–0.95). The introduction in regions of high gastric cancer incidence of population-based H. pylori screening and treatment programmes, with a scientifically valid assessment of programme processes, feasibility, effectiveness and possible adverse consequences, would impact the incidence of H. pylori-induced gastric cancer. Given the recent molecular understanding of the oncogenic role of CagA, targeting H. pylori screening and treatment programmes in populations with a high prevalence of H. pylori CagA-positive strains, particularly the more oncogenic East Asian H. pylori CagA strains, may be worth further investigation to optimise the benefits of such strategies. Full article

This article summarizes the main findings concerning Helicobacter pylori associated with gastric MALT lymphoma (GML). Considered together, GML strains based on their virulence factor profile appear to be less virulent than those associated with peptic ulcers or gastric adenocarcinoma. A particular Lewis antigen profile has been identified in GML strains and could represent an alternative adaptive mechanism to escape the host immune response thereby allowing continuous antigenic stimulation of infiltrating lymphocytes. Full article

Gastric cancer is a leading cause of cancer death worldwide. Diet, obesity, smoking and chronic infections, especially with Helicobacter pylori, contribute to stomach cancer development. H. pylori possesses a variety of virulence factors including encoded factors from the cytotoxin‐associated gene pathogenicity island (cagPAI) or vacuolating cytotoxin A (VacA). Most of the cagPAI‐encoded products form a type 4 secretion system (T4SS), a pilus‐like macromolecular transporter, which translocates CagA into the cytoplasm of the host cell. Only H. pylori strains carrying the cagPAI induce the transcription factor NF‐κB, but CagA and VacA are dispensable for direct NF‐κB activation. NF‐κB‐driven gene products include cytokines/chemokines, growth factors, anti‐apoptotic factors, angiogenesis regulators and metalloproteinases. Many of the genes transcribed by NF‐κB promote gastric carcinogenesis. Since it has been shown that chemotherapy‐caused cellular stress could elicit activation of the survival factor NF‐κB, which leads to acquisition of chemoresistance, the NF‐κB system is recommended for therapeutic targeting. Research is motivated for further search of predisposing conditions, diagnostic markers and efficient drugs to improve significantly the overall survival of patients. In this review, we provide an overview about mechanisms and consequences of NF‐κB activation in gastric mucosa in order to understand the role of NF‐κB in gastric carcinogenesis. Full article

Helicobacter pylori is a highly successful human bacterium, which is exceptionally equipped to persistently inhabit the human stomach. Colonization by this pathogen is associated with gastric disorders ranging from chronic gastritis and peptic ulcers to cancer. Highly virulent H. pylori strains express the well-established adhesins BabA/B, SabA, AlpA/B, OipA, and HopQ, and a type IV secretion system (T4SS) encoded by the cag pathogenicity island (PAI). The adhesins ascertain intimate bacterial contact to gastric epithelial cells, while the T4SS represents an extracellular pilus-like structure for the translocation of the effector protein CagA. Numerous T4SS components including CagI, CagL, CagY, and CagA have been shown to target the integrin-β₁ receptor followed by translocation of CagA across the host cell membrane. The interaction of CagA with membrane-anchored phosphatidylserine and CagA-containing outer membrane vesicles may also play a role in the delivery process. Translocated CagA undergoes tyrosine phosphorylation in C-terminal EPIYA-repeat motifs by oncogenic Src and Abl kinases. CagA then interacts with an array of host signaling proteins followed by their activation or inactivation in phosphorylation-dependent and phosphorylation-independent fashions. We now count about 25 host cell binding partners of intracellular CagA, which represent the highest quantity of all currently known virulence-associated effector proteins in the microbial world. Here we review the research progress in characterizing interactions of CagA with multiple host cell receptors in the gastric epithelium, including integrin-β₁, EGFR, c-Met, CD44, E-cadherin, and gp130. The contribution of these interactions to H. pylori colonization, signal transduction, and gastric pathogenesis is discussed. Full article

By modulating important properties of eukaryotic cells, many bacterial protein toxins highjack host signalling pathways to create a suitable niche for the pathogen to colonize and persist. Helicobacter pylori VacA is paradigm of pore-forming toxins which contributes to the pathogenesis of peptic ulceration. Several cellular receptors have been described for VacA, which exert different effects on epithelial and immune cells. The crystal structure of VacA p55 subunit might be important for elucidating details of receptor interaction and pore formation. Here we discuss the multiple signalling activities of this important toxin and the molecular crosstalk between VacA and other virulence factors. Full article