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Nahian M, Khan MR, Rahman F, Reza HM, Bayil I, Nodee TA, Basher T, Sany MR, Munmun RN, Habib SMA, Mazumder L, Acharjee M. Immunoinformatic strategy for developing multi-epitope subunit vaccine against Helicobacter pylori. PLoS One 2025; 20:e0318750. [PMID: 39919064 PMCID: PMC11805379 DOI: 10.1371/journal.pone.0318750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Accepted: 01/20/2025] [Indexed: 02/09/2025] Open
Abstract
Helicobacter pylori is a gram-negative bacterium that persistently infects the human stomach, leading to peptic ulcers, gastritis, and an increased risk of gastric cancer. The extremophilic characteristics of this bacterium make it resistant to current drug treatments, and there are no licensed vaccines available against H. pylori. Computational approaches offer a viable alternative for designing antigenic, stable, and safe vaccines to control infections caused by this pathogen. In this study, we employed an immunoinformatic strategy to design a set of candidate multi-epitope subunit vaccines by combining the most potent B and T cell epitopes from three targeted antigenic proteins (BabA, CagA, and VacA). Out of the 12 hypothetical vaccines generated, two (HP_VaX_V1 and HP_VaX_V2) were found to be strongly immunogenic, non-allergenic, and structurally stable. The proposed vaccine candidates were evaluated based on population coverage, molecular docking, immune simulations, codon adaptation, secondary mRNA structure, and in silico cloning. The vaccine candidates exhibited antigenic scores of 1.19 and 1.01, with 93.5% and 90.4% of the most rama-favored regions, respectively. HP_VaX_V1 and HP_VaX_V2 exhibited the strongest binding affinity towards TLR-7 and TLR-8, as determined by molecular docking simulations (ΔG = -20.3 and -20.9, respectively). Afterward, multi-scale normal mode analysis simulation revealed the structural flexibility and stability of vaccine candidates. Additionally, immune simulations showed elevated levels of cell-mediated immunity, while repeated exposure simulations indicated rapid antigen clearance. Finally, in silico cloning was performed using the expression vector pET28a (+) with optimized restriction sites to develop a viable strategy for large-scale production of the chosen vaccine constructs. These analyses suggest that the proposed vaccines may elicit potent immune responses against H. pylori, but laboratory validation is needed to verify their safety and immunogenicity.
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Affiliation(s)
- Md. Nahian
- Department of Microbiology, Jagannath University, Dhaka, Bangladesh
| | - Md. Rasel Khan
- Department of Microbiology, Jagannath University, Dhaka, Bangladesh
| | - Fabiha Rahman
- Department of Microbiology, Jagannath University, Dhaka, Bangladesh
| | - Hossain Mohammed Reza
- Faculty of Life and Health Sciences, School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland
| | - Imren Bayil
- Department of Bioinformatics and Computational Biology, Gaziantep University, Gaziantep, Turkey
| | | | - Tabassum Basher
- Department of Microbiology, Jagannath University, Dhaka, Bangladesh
| | | | | | | | - Lincon Mazumder
- Department of Microbiology, Jagannath University, Dhaka, Bangladesh
| | - Mrityunjoy Acharjee
- Department of Microbiology, Stamford University Bangladesh, Dhaka, Bangladesh
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Muñoz AB, Stepanian J, Solano‐Gutierrez JS, Vale FF, Trespalacios‐Rangel AA. Helicobacter pylori Infection in Colombia: Phylogeny, Resistome, and Virulome. APMIS 2025; 133:e70003. [PMID: 39930978 PMCID: PMC11811748 DOI: 10.1111/apm.70003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 11/06/2024] [Accepted: 01/27/2025] [Indexed: 02/13/2025]
Abstract
Helicobacter pylori is a successful etiologic gastric agent that reaches a prevalence around 80% in Colombia. This bacterium is extremely diverse and has shown a phylogeographic pattern. The objective of this study was to perform an analysis of genomic epidemiology of H. pylori in Colombia. We enriched our set of 29 newly sequenced Colombian H. pylori genomes with additional data from public databases, reaching a total of 221 genomes in our dataset. Phylogenetic characterization was carried out using MLST and whole genome SNP analysis. We also performed a characterized the diversity of virulence factors and mutations associated with antimicrobial resistance. Phylogenetic analyzes showed two new Colombian H. pylori clades. Furthermore, many virulence genotype combinations were found, mutations associated with resistance were found for all the studied antibiotics, highlighting 14.4% of the genomes presented profiles associated with resistance to more than one family of antibiotics. Our analyzes described the genomics of Colombian H. pylori and verify the presence of a population group formed exclusively by Colombian isolates. We demonstrated the great diversity among the isolates and that the analysis by comparative genomics of H. pylori are valuable tools to assess the diversity, virulence, and resistance of H. pylori.
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Affiliation(s)
- Angela B. Muñoz
- Infectious Diseases Research Group, Microbiology Department, Sciences FacultyPontificia Universidad JaverianaBogotáColombia
- Health Sciences FacultyUniversidad Colegio Mayor de CundinamarcaBogotáColombia
| | - Johanna Stepanian
- Infectious Diseases Research Group, Microbiology Department, Sciences FacultyPontificia Universidad JaverianaBogotáColombia
| | - Juan S. Solano‐Gutierrez
- Texas Tech University—School of Veterinary MedicineAmarilloTexasUSA
- Texas Center for Comparative Cancer Research (TC3R)AmarilloTexasUSA
| | - Filipa F. Vale
- BioISI—Instituto de Biosistemas e Ciências Integrativas, Faculdade de CiênciasUniversidade de LisboaLisboaPortugal
- Research Institute for Medicines (iMed.ULisboa), Faculty of PharmacyUniversidade de LisboaLisboaPortugal
| | - Alba A. Trespalacios‐Rangel
- Infectious Diseases Research Group, Microbiology Department, Sciences FacultyPontificia Universidad JaverianaBogotáColombia
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Singh S, Sharma AK, Som A, Gehlot V, Mahant S, Sharma P, Das K, Das R. Molecular characterization and phylogenetic analysis of babA gene of Helicobacter pylori isolated from Indian patients with gastrointestinal diseases. Gene 2024; 920:148526. [PMID: 38703866 DOI: 10.1016/j.gene.2024.148526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 04/16/2024] [Accepted: 05/01/2024] [Indexed: 05/06/2024]
Abstract
INTRODUCTION Outer membrane protein (OMP) of Helicobacter pylori (H. pylori) i.e., blood group antigen binding adhesin (babA) is responsible for the attachment of H. pylori in the gastric epithelium. Its adherence is causative for gastric pathology such as gastritis, peptic ulcer disease (PUD), or digestive tract disorders like erosive reflux disease (ERD) and (NERD) non-erosive reflux disease and together called Gastroesophageal reflux disease (GERD). BabA manifests rapid and varied selection via substitution of amino acid in its Leb-carbohydrate binding domain (CBD) which enables better binding preferences for distinct human populations and ABO blood group phenotypes. The positive evolutionary selection of the pathogenic factor of this genetically diverse bacterium has enabled it to adapt to the host gastric environment. Analyzing the association of virulent genes (cagA, vacA) and babA will help us better understand bacteria's pathogenicity. METHOD 109 H. pylori strains from patients with distinct gastrointestinal diseases were genotyped using Polymerase Chain Reaction(PCR) for cagA, vacA, and babA followed by Sanger sequencing and phylogenetic analysis. RESULT In the babA + ve genotype, a statistically significant association with p = 0.04 and < 0.0001 is seen in gastritis and ERD respectively. A significant association of genotype vacAs1m2 (p = 0.0002) was seen in gastritis, vacAs1m1 (p = 0.02) in NERD, vacAs1m1 (p < 0.0001) and vacAs1m2 (p = 0.002) in ERD. This relationship helps to detect gastritis or ERD where BabA gene can be used as an independent marker for detecting their presence. CONCLUSION The appearance of variants within distinct disease categories is due to local genetic variation.
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Affiliation(s)
- Sarika Singh
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, UP, India.
| | - Amresh Kumar Sharma
- Centre of Bioinformatics, Institute of Interdisciplinary Studies, University of Allahabad, Prayagraj 211002, UP, India.
| | - Anup Som
- Centre of Bioinformatics, Institute of Interdisciplinary Studies, University of Allahabad, Prayagraj 211002, UP, India.
| | - Valentina Gehlot
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, UP, India.
| | - Shweta Mahant
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, UP, India.
| | - Prateek Sharma
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, UP, India.
| | - Kunal Das
- Department of Gastroenterology, Yashoda super specialty Hospital, Ghaziabad, 201001, U.P, India.
| | - Rajashree Das
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, UP, India.
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Drnovsek J, Homan M, Zidar N, Smid LM. Pathogenesis and potential reversibility of intestinal metaplasia - a milestone in gastric carcinogenesis. Radiol Oncol 2024; 58:186-195. [PMID: 38643513 PMCID: PMC11165985 DOI: 10.2478/raon-2024-0028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 03/19/2024] [Indexed: 04/23/2024] Open
Abstract
BACKGROUND Non-cardia gastric cancer remains a major cause of cancer-related mortality worldwide, despite declining incidence rates in many industrialized countries. The development of intestinal-type gastric cancer occurs through a multistep process in which normal mucosa is sequentially transformed into hyperproliferative epithelium, followed by metaplastic processes leading to carcinogenesis. Chronic infection with Helicobacter pylori is the primary etiological agent that causes chronic inflammation of the gastric mucosa, induces atrophic gastritis, and can lead to intestinal metaplasia and dysplasia. Both intestinal metaplasia and dysplasia are precancerous lesions, in which gastric cancer is more likely to occur. Atrophic gastritis often improves after eradication of Helicobacter pylori; however, the occurrence of intestinal metaplasia has been traditionally regarded as "the point of no return" in the carcinogenesis sequence. Helicobacter pylori eradication heals non-atrophic chronic gastritis, may lead to regression of atrophic gastritis, and reduces the risk of gastric cancer in patients with these conditions. In this article, we discuss the pathogenesis, epigenomics, and reversibility of intestinal metaplasia and briefly touch upon potential treatment strategy. CONCLUSIONS Gastric intestinal metaplasia no longer appears to be an irreversible precancerous lesion. However, there are still many controversies regarding the improvement of intestinal metaplasia after Helicobacter pylori eradication.
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Affiliation(s)
- Jan Drnovsek
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Matjaz Homan
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Gastroenterology, Hepatology and Nutrition, University Children’s Hospital, Ljubljana, Slovenia
| | - Nina Zidar
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Lojze M Smid
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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Somiah T, Gebremariam HG, Zuo F, Smirnova K, Jonsson AB. Lactate causes downregulation of Helicobacter pylori adhesin genes sabA and labA while dampening the production of proinflammatory cytokines. Sci Rep 2022; 12:20064. [PMID: 36414643 PMCID: PMC9681763 DOI: 10.1038/s41598-022-24311-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 11/14/2022] [Indexed: 11/24/2022] Open
Abstract
Chronic inflammation induced by Helicobacter pylori is strongly associated with gastric cancer development, which is influenced by both bacterial virulence and host genetics. The sialic acid-binding adhesin SabA and the MUC5AC-binding adhesin LabA are important H. pylori virulence factors that facilitate adhesion of the bacterium, which is a crucial step in colonization. Lactate utilization has been reported to play a key role in the pathogenicity of different bacterial species. However, this is poorly understood in H. pylori. In this study, we investigated the effect of lactate on H. pylori adhesin gene expression and the regulation of host inflammatory cytokines. We show that the bacterial adhesins SabA and LabA were downregulated at the transcriptional level during incubation of H. pylori with lactate. Downregulation of sabA required the involvement of the two-component system ArsRS, while labA was regulated via the CheA/CheY system, indicating differences in the regulation of these genes in response to lactate. The levels of the proinflammatory cytokines TNF and IL-6 in H. pylori-stimulated macrophages were reduced when lactate was present. Interestingly, glucose did not prevent the secretion of these cytokines. Taken together, our data suggest that lactate affects H. pylori adhesin gene expression and the host response upon infection.
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Affiliation(s)
- Tanvi Somiah
- grid.10548.380000 0004 1936 9377Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrheniusväg 20C, 10691 Stockholm, Sweden
| | - Hanna G. Gebremariam
- grid.10548.380000 0004 1936 9377Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrheniusväg 20C, 10691 Stockholm, Sweden
| | - Fanglei Zuo
- grid.10548.380000 0004 1936 9377Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrheniusväg 20C, 10691 Stockholm, Sweden
| | - Ksenija Smirnova
- grid.10548.380000 0004 1936 9377Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrheniusväg 20C, 10691 Stockholm, Sweden
| | - Ann-Beth Jonsson
- grid.10548.380000 0004 1936 9377Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrheniusväg 20C, 10691 Stockholm, Sweden
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Svarval AV, Starkova DA, Ferman RS. Detection of the babA2 adhesin protein gene in Helicobacter pylori clinical isolates. Klin Lab Diagn 2022; 67:538-543. [PMID: 36099464 DOI: 10.51620/0869-2084-2022-67-9-538-543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
The study compared the effectiveness of two different primer sets for detecting and evaluating the prevalence of the babA2 gene in 52 H. pylori clinical isolates from patients with chronic gastritis (n=32), duodenal ulcer (n=16) and stomach cancer (n=4) in St. Petersburg, Russia. The PCR was used for detection of the babA2 gene with 271 bp and 832 bp primer sets followed by sequencing of the PCR-amplicons. The largest proportion of babA2-positive strains - 90.4% (47/52) was detected using a 271 bp PCR primer set. Detection of the 832 bp PCR positive samples was observed only in 51.9% of cases (27/52). The largest proportion of babA2-positive strains - 90.4% (47/52) was detected using 271 bp PCR primer set; detection of 832 bp PCR product was observed only in 51.9% cases (27/52), however, there were no significant differences in the babA2 gene detection rates (p>0.05). Bioinformatic analysis revealed a homology of Sanger sequenced PCR products 271 bp and 832 bp of babA2 gene with regions of the babA2, babA1, and chimeric babA/B genes of H. pylori strains annotated in the NCBI database. Regardless of the primer set used, the presence of babA2 was not significantly associated with duodenal ulcer nor gastric cancer (p>0.05). The combination of the three babA2, cagA, and vacAs1 genes did not reveal any association between the presence of babA2 gene and cagA/vacAs1 genes in H. pylori strains (p>0.05). Thus, none of the two primer sets (271 bp and 832 bp) appears sufficiently informative for detecting the babA2 gene to assess virulence of H. pylori Russian strains.
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Nath AN, Retnakumar RJ, Francis A, Chhetri P, Thapa N, Chattopadhyay S. Peptic Ulcer and Gastric Cancer: Is It All in the Complex Host-Microbiome Interplay That Is Encoded in the Genomes of "Us" and "Them"? Front Microbiol 2022; 13:835313. [PMID: 35547123 PMCID: PMC9083406 DOI: 10.3389/fmicb.2022.835313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/18/2022] [Indexed: 11/13/2022] Open
Abstract
It is increasingly being recognized that severe gastroduodenal diseases such as peptic ulcer and gastric cancer are not just the outcomes of Helicobacter pylori infection in the stomach. Rather, both diseases develop and progress due to the perfect storms created by a combination of multiple factors such as the expression of different H. pylori virulence proteins, consequent human immune responses, and dysbiosis in gastrointestinal microbiomes. In this mini review, we have discussed how the genomes of H. pylori and other gastrointestinal microbes as well as the genomes of different human populations encode complex and variable virulome–immunome interplay, which influences gastroduodenal health. The heterogeneities that are encrypted in the genomes of different human populations and in the genomes of their respective resident microbes partly explain the inconsistencies in clinical outcomes among the H. pylori-infected people.
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Affiliation(s)
- Angitha N Nath
- Rajiv Gandhi Centre for Biotechnology, Trivandrum, India
| | - R J Retnakumar
- Rajiv Gandhi Centre for Biotechnology, Trivandrum, India.,Manipal Academy of Higher Education, Manipal, India
| | - Ashik Francis
- Rajiv Gandhi Centre for Biotechnology, Trivandrum, India
| | - Prakash Chhetri
- Department of Zoology, Biotech Hub, Nar Bahadur Bhandari Degree College, Tadong, India
| | - Namrata Thapa
- Department of Zoology, Biotech Hub, Nar Bahadur Bhandari Degree College, Tadong, India
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Sijmons D, Guy AJ, Walduck AK, Ramsland PA. Helicobacter pylori and the Role of Lipopolysaccharide Variation in Innate Immune Evasion. Front Immunol 2022; 13:868225. [PMID: 35634347 PMCID: PMC9136243 DOI: 10.3389/fimmu.2022.868225] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 04/04/2022] [Indexed: 11/30/2022] Open
Abstract
Helicobacter pylori is an important human pathogen that infects half the human population and can lead to significant clinical outcomes such as acute and chronic gastritis, duodenal ulcer, and gastric adenocarcinoma. To establish infection, H. pylori employs several mechanisms to overcome the innate and adaptive immune systems. H. pylori can modulate interleukin (IL) secretion and innate immune cell function by the action of several virulence factors such as VacA, CagA and the type IV secretion system. Additionally, H. pylori can modulate local dendritic cells (DC) negatively impacting the function of these cells, reducing the secretion of immune signaling molecules, and influencing the differentiation of CD4+ T helper cells causing a bias to Th1 type cells. Furthermore, the lipopolysaccharide (LPS) of H. pylori displays a high degree of phase variation and contains human blood group carbohydrate determinants such as the Lewis system antigens, which are proposed to be involved in molecular mimicry of the host. Lastly, the H. pylori group of outer membrane proteins such as BabA play an important role in attachment and interaction with host Lewis and other carbohydrate antigens. This review examines the various mechanisms that H. pylori utilises to evade the innate immune system as well as discussing how the structure of the H. pylori LPS plays a role in immune evasion.
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Affiliation(s)
- Daniel Sijmons
- School of Science, RMIT University, Melbourne, VIC, Australia
| | - Andrew J. Guy
- School of Science, RMIT University, Melbourne, VIC, Australia
- ZiP Diagnostics, Collingwood, VIC, Australia
| | - Anna K. Walduck
- School of Science, RMIT University, Melbourne, VIC, Australia
| | - Paul A. Ramsland
- School of Science, RMIT University, Melbourne, VIC, Australia
- Department of Immunology, Monash University, Melbourne, VIC, Australia
- Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia
- *Correspondence: Paul A. Ramsland,
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Roy R, Jonniya NA, Sk MF, Kar P. Comparative Structural Dynamics of Isoforms of Helicobacter pylori Adhesin BabA Bound to Lewis b Hexasaccharide via Multiple Replica Molecular Dynamics Simulations. Front Mol Biosci 2022; 9:852895. [PMID: 35586194 PMCID: PMC9108286 DOI: 10.3389/fmolb.2022.852895] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/30/2022] [Indexed: 11/30/2022] Open
Abstract
BabA of Helicobacter pylori is the ABO blood group antigen-binding adhesin. Despite considerable diversity in the BabA sequence, it shows an extraordinary adaptation in attachment to mucosal layers. In the current study, multiple replica molecular dynamics simulations were conducted in a neutral aqueous solution to elucidate the conformational landscape of isoforms of BabA bound to Lewis b (Leb) hexasaccharide. In addition, we also investigated the underlying molecular mechanism of the BabA-glycan complexation using the MM/GBSA scheme. The conformational dynamics of Leb in the free and protein-bound states were also studied. The carbohydrate-binding site across the four isoforms was examined, and the conformational variability of several vital loops was observed. The cysteine–cysteine loops and the two diversity loops (DL1 and DL2) were identified to play an essential role in recognizing the glycan molecule. The flexible crown region of BabA was stabilized after association with Leb. The outward movement of the DL2 loop vanished upon ligand binding for the Spanish specialist strain (S381). Our study revealed that the S831 strain shows a stronger affinity to Leb than other strains due to an increased favorable intermolecular electrostatic contribution. Furthermore, we showed that the α1-2-linked fucose contributed most to the binding by forming several hydrogen bonds with key amino acids. Finally, we studied the effect of the acidic environment on the BabA-glycan complexation via constant pH MD simulations, which showed a reduction in the binding free energy in the acidic environment. Overall, our study provides a detailed understanding of the molecular mechanism of Leb recognition by four isoforms of H. pylori that may help the development of therapeutics targeted at inhibiting H. pylori adherence to the gastric mucosa.
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A new approach against Helicobacter pylori using plants and its constituents: A review study. Microb Pathog 2022; 168:105594. [PMID: 35605740 DOI: 10.1016/j.micpath.2022.105594] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 05/11/2022] [Accepted: 05/15/2022] [Indexed: 02/07/2023]
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Lima de Souza Gonçalves V, Cordeiro Santos ML, Silva Luz M, Santos Marques H, de Brito BB, França da Silva FA, Souza CL, Oliveira MV, de Melo FF. From Helicobacter pylori infection to gastric cancer: Current evidence on the immune response. World J Clin Oncol 2022; 13:186-199. [PMID: 35433296 PMCID: PMC8966509 DOI: 10.5306/wjco.v13.i3.186] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/31/2021] [Accepted: 02/15/2022] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the result of a multifactorial process whose main components are infection by Helicobacter pylori (H. pylori), bacterial virulence factors, host immune response and environmental factors. The development of the neoplastic microenvironment also depends on genetic and epigenetic changes in oncogenes and tumor suppressor genes, which results in deregulation of cell signaling pathways and apoptosis process. This review summarizes the main aspects of the pathogenesis of GC and the immune response involved in chronic inflammation generated by H. pylori.
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Affiliation(s)
| | - Maria Luísa Cordeiro Santos
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Hanna Santos Marques
- Universidade Estadual do Sudoeste da Bahia, Campus Vitória da Conquista, Vitória da Conquista 45083-900, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Cláudio Lima Souza
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Márcio Vasconcelos Oliveira
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
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12
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Nguyen H, Herrmann F, König S, Goycoolea F, Hensel A. Structural characterization of the carbohydrate and protein part of arabinogalactan protein from Basella alba stem and antiadhesive activity of polysaccharides from B. alba against Helicobacter pylori. Fitoterapia 2022; 157:105132. [DOI: 10.1016/j.fitote.2022.105132] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/17/2022] [Accepted: 01/17/2022] [Indexed: 01/17/2023]
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13
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Valdez-Salazar HA, Ares MA, Fernández FJ, Ibarra JA, Torres J, Bustamante VH, De la Cruz MA. Long-chain fatty acids alter transcription of Helicobacter pylori virulence and regulatory genes. PeerJ 2021; 9:e12270. [PMID: 34760355 PMCID: PMC8567857 DOI: 10.7717/peerj.12270] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 09/17/2021] [Indexed: 12/18/2022] Open
Abstract
Infection with Helicobacter pylori is one of the most important risk factors for developing gastric cancer (GC). The type IV secretion system (T4SS) encoded in the cag pathogenicity island is the main virulence factor of H. pylori associated with GC. Additionally, other virulence factors have been shown to play a role in the H. pylori virulence, such as vacuolizing cytotoxin (VacA), urease, flagella, and adhesins. Long-chain fatty acids (LCFAs) are signaling molecules that affect the transcription of virulence genes in several pathogenic bacteria such as Salmonella enterica, Vibrio cholerae, Pseudomonas aeruginosa and Mycobacterium tuberculosis. However, the effect of LCFAs on the transcription of H. pylori virulence and regulatory genes remains unknown. Here we analyzed whether the transcription of virulence genes that encode T4SS and cellular envelope components, flagellins, adhesins, toxins, urease, as well as the transcription of different regulatory genes of the H. pylori strain 26695, are altered by the presence of five distinct LCFAs: palmitic, stearic, oleic, linoleic, and linolenic acids. Palmitic and oleic acids up-regulated the transcription of most of the virulence genes tested, including cagL, cagM, flaB, sabA, mraY and vacA, as well as that of the genes encoding the transcriptional regulators NikR, Fur, CheY, ArsR, FlgR, HspR, HsrA, Hup, and CrdR. In contrast, the other LCFAs differentially affected the transcription of the virulence and regulatory genes assessed. Our data show that LCFAs can act as signaling molecules that control the transcription of the H. pylori virulome.
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Affiliation(s)
- Hilda A Valdez-Salazar
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Instituto Mexicano del Seguro Social, Mexico City, Mexico.,Posgrado en Biología Experimental, DCBS., Universidad Autónoma Metropolitana (UAM) Iztapalapa, Mexico City, Mexico
| | - Miguel A Ares
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Instituto Mexicano del Seguro Social, Mexico City, Mexico.,Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Francisco J Fernández
- Laboratorio de Ingeniería Genética y Metabolismo Secundario, Departamento de Biotecnología, Universidad Autónoma Metropolitana, Mexico City, Mexico
| | - J Antonio Ibarra
- Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Javier Torres
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Víctor H Bustamante
- Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, Mexico
| | - Miguel A De la Cruz
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Instituto Mexicano del Seguro Social, Mexico City, Mexico
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Helicobacter pylori BabA-SabA Key Roles in the Adherence Phase: The Synergic Mechanism for Successful Colonization and Disease Development. Toxins (Basel) 2021; 13:toxins13070485. [PMID: 34357957 PMCID: PMC8310295 DOI: 10.3390/toxins13070485] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/03/2021] [Accepted: 07/07/2021] [Indexed: 01/21/2023] Open
Abstract
Helicobacter pylori is a pathogenic microorganism that successfully inhabits the human stomach, colonizing it by producing several virulence factors responsible for preventing host self-defense mechanisms. The adherence mechanism to gastric mucosal tissue is one of the most important processes for effective colonization in the stomach. The blood group antigen-binding adhesion (BabA) and sialic acid-binding adherence (SabA) are two H. pylori outer membrane proteins able to interact with antigens in the gastroduodenal tract. H. pylori possesses several mechanisms to control the regulation of both BabA and SabA in either the transcriptional or translational level. BabA is believed to be the most important protein in the early infection phase due to its ability to interact with various Lewis antigens, whereas SabA interaction with sialylated Lewis antigens may prove important for the adherence process in the inflamed gastric mucosal tissue in the ongoing-infection phase. The adherence mechanisms of BabA and SabA allow H. pylori to anchor in the gastric mucosa and begin the colonization process.
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de Brito BB, Lemos FFB, Carneiro CDM, Viana AS, Barreto NMPV, Assis GADS, Braga BDC, Santos MLC, Silva FAFD, Marques HS, Silva NOE, de Melo FF. Immune response to Helicobacter pylori infection and gastric cancer development. World J Meta-Anal 2021; 9:257-276. [DOI: 10.13105/wjma.v9.i3.257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/24/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
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A bacterial small RNA regulates the adaptation of Helicobacter pylori to the host environment. Nat Commun 2021; 12:2085. [PMID: 33837194 PMCID: PMC8035401 DOI: 10.1038/s41467-021-22317-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 03/10/2021] [Indexed: 12/15/2022] Open
Abstract
Long-term infection of the stomach with Helicobacter pylori can cause gastric cancer. However, the mechanisms by which the bacteria adapt to the stomach environment are poorly understood. Here, we show that a small non-coding RNA of H. pylori (HPnc4160, also known as IsoB or NikS) regulates the pathogen’s adaptation to the host environment as well as bacterial oncoprotein production. In a rodent model of H. pylori infection, the genomes of bacteria isolated from the stomach possess an increased number of T-repeats upstream of the HPnc4160-coding region, and this leads to reduced HPnc4160 expression. We use RNA-seq and iTRAQ analyses to identify eight targets of HPnc4160, including genes encoding outer membrane proteins and oncoprotein CagA. Mutant strains with HPnc4160 deficiency display increased colonization ability of the mouse stomach, in comparison with the wild-type strain. Furthermore, HPnc4160 expression is lower in clinical isolates from gastric cancer patients than in isolates derived from non-cancer patients, while the expression of HPnc4160’s targets is higher in the isolates from gastric cancer patients. Therefore, the small RNA HPnc4160 regulates H. pylori adaptation to the host environment and, potentially, gastric carcinogenesis. Long-term infection of the stomach with Helicobacter pylori can cause gastric cancer. Here, Kinoshita-Daitoku et al. show that a small non-coding RNA of H. pylori regulates bacterial adaptation to the stomach environment and bacterial oncoprotein production.
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Banga Ndzouboukou JL, Lei Q, Ullah N, Zhang Y, Hao L, Fan X. Helicobacter pylori adhesins: HpaA a potential antigen in experimental vaccines for H. pylori. Helicobacter 2021; 26:e12758. [PMID: 33259676 DOI: 10.1111/hel.12758] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 08/14/2020] [Accepted: 09/01/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Helicobacter pylori is a gram-negative bacterium involved in many gastric pathologies such as ulcers and cancers. Although the treatment for this infection has existed for several years, the development of a vaccine is nevertheless necessary to reduce the severe forms of the disease. For more than three decades, many advances have been made particularly in the understanding of virulence factors as well as the pathogenesis of gastric diseases caused by H. pylori. Among these key virulence factors, specific antigens have been identified: Urease, Vacuolating cytotoxin A (VacA), Cytotoxin-associated gene A (CagA), Blood group antigen-binding adhesin (BabA), H. pylori adhesin A (HpaA), and others. OBJECTIVES This review will focus on H. pylori adhesins, in particular, on HpaA and on the current knowledge of H. pylori vaccines. METHODS All of the information included in this review was retrieved from published studies on H. pylori adhesins in H. pylori infections. RESULTS These proteins, used in their native or recombinant forms, induce protection against H. pylori in experimental animal models. CONCLUSION H. pylori adhesins are known to be promising candidate vaccines against H. pylori. Future research should be carried out on adhesins, in particular, on HpaA.
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Affiliation(s)
- Jo-Lewis Banga Ndzouboukou
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Lei
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nadeem Ullah
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yandi Zhang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Hao
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xionglin Fan
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Crowley E, Hussey S. Helicobacter pylori in Childhood. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:275-292.e12. [DOI: 10.1016/b978-0-323-67293-1.00027-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Baj J, Forma A, Sitarz M, Portincasa P, Garruti G, Krasowska D, Maciejewski R. Helicobacter pylori Virulence Factors-Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment. Cells 2020; 10:27. [PMID: 33375694 PMCID: PMC7824444 DOI: 10.3390/cells10010027] [Citation(s) in RCA: 198] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer constitutes one of the most prevalent malignancies in both sexes; it is currently the fourth major cause of cancer-related deaths worldwide. The pathogenesis of gastric cancer is associated with the interaction between genetic and environmental factors, among which infection by Helicobacter pylori (H. pylori) is of major importance. The invasion, survival, colonization, and stimulation of further inflammation within the gastric mucosa are possible due to several evasive mechanisms induced by the virulence factors that are expressed by the bacterium. The knowledge concerning the mechanisms of H. pylori pathogenicity is crucial to ameliorate eradication strategies preventing the possible induction of carcinogenesis. This review highlights the current state of knowledge and the most recent findings regarding H. pylori virulence factors and their relationship with gastric premalignant lesions and further carcinogenesis.
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Affiliation(s)
- Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-400 Lublin, Poland;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Monika Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Danuta Krasowska
- Department of Dermatology, Venerology and Paediatric Dermatology of Medical University of Lublin, 20-081 Lublin, Poland;
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20
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Sonkar C, Verma T, Chatterji D, Jain AK, Jha HC. Status of kinases in Epstein-Barr virus and Helicobacter pylori Coinfection in gastric Cancer cells. BMC Cancer 2020; 20:925. [PMID: 32993565 PMCID: PMC7523314 DOI: 10.1186/s12885-020-07377-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 09/03/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) and Epstein - Barr virus (EBV) plays a significant role in aggressive gastric cancer (GC). The investigation of genes associated with these pathogens and host kinases may be essential to understand the early and dynamic progression of GC. AIM The study aimed to demonstrate the coinfection of EBV and H. pylori in the AGS cells through morphological changes, expression of the kinase and the probable apoptotic pathways. METHODS Genomic DNA isolation of H. pylori and its characterization from clinical samples were performed. RT-qPCR of kinases was applied to scrutinize the gene expression of kinases in co-infected GC in a direct and indirect (separated through insert size 0.45 μm) H. pylori infection set up. Morphological changes in co-infected GC were quantified by measuring the tapering ends of gastric epithelial cells. Gene expression profiling of apoptotic genes was assessed through RT-qPCR. RESULTS An interleukin-2-inducible T-cell kinase (ITK) showed significant upregulation with indirect H. pylori infection. Moreover, Ephrin type-B receptor six precursors (EPHB6) and Tyrosine-protein kinase Fyn (FYN) showed significant upregulation with direct coinfection. The tapering ends in AGS cells were found to be extended after 12 h. A total of 24 kinase genes were selected, out of which EPHB6, ITK, FYN, and TYK2 showed high expression as early as 12 h. These kinases may lead to rapid morphological changes in co-infected gastric cells. Likewise, apoptotic gene expression such as APAF-1 and Bcl2 family genes such as BAD, BID, BIK, BIM, BAX, AND BAK were significantly down-regulated in co-infected AGS cells. CONCLUSION All the experiments were performed with novel isolates of H. pylori isolated from central India, for the functional assessment of GC. The effect of coinfection with EBV was more profoundly observed on morphological changes in AGS cells at 12 h as quantified by measuring the tapering of ends. This study also identifies the kinase and apoptotic genes modulated in co-infected cells, through direct and indirect approaches. We report that ITK, EPHB6, TYK2, FYN kinase are enhanced, whereas apoptotic genes such as APAF-1, BIK, FASL, BAX are significantly down-regulated in AGS cells coinfected with EBV and H. pylori.
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Affiliation(s)
- Charu Sonkar
- The Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Room no. 302, School Building, IIT Indore, Khandwa Road, Simrol, Indore, 453552, India
| | - Tarun Verma
- The Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Room no. 302, School Building, IIT Indore, Khandwa Road, Simrol, Indore, 453552, India
| | - Debi Chatterji
- Choithram Hospital and Research Centre Indore, Indore, Madhya Pradesh, India
| | - Ajay Kumar Jain
- Choithram Hospital and Research Centre Indore, Indore, Madhya Pradesh, India
| | - Hem Chandra Jha
- The Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Room no. 302, School Building, IIT Indore, Khandwa Road, Simrol, Indore, 453552, India.
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Proteomic and transcriptomic studies of BGC823 cells stimulated with Helicobacter pylori isolates from gastric MALT lymphoma. PLoS One 2020; 15:e0238379. [PMID: 32915799 PMCID: PMC7485896 DOI: 10.1371/journal.pone.0238379] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 08/15/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The correlation between the infection of H. pylori and the occurrence of gastric MALT lymphoma (GML) has been well documented. However, the mechanism of how GML is caused by this bacterium is not well understood, although some immunologic mechanisms are thought to be involved. MATERIALS AND METHODS In this study, we performed both transcriptomic and proteomic analyses on gastric cancer cells infected by H. pylori isolates from GML patients and the gastric ulcer strain 26695 to investigate the differentially expressed molecular signatures that were induced by GML isolates. RESULTS Transcriptomic analyses revealed that the differentially expressed genes (DEGs) were mainly related to binding, catalytic activity, signal transducer activity, molecular transducer activity, nucleic acid binding transcription factor activity, and molecular function regulator. Fifteen pathways, including the Wnt signaling pathway, the mTOR signaling pathway, the NOD-like receptor signaling pathway and the Hippo signaling pathway, were revealed to be related to GML isolates. Proteomic analyses results showed that there were 116 differentially expressed proteins (DEPs). Most of these DEPs were associated with cancer, and 29 have been used as biomarkers for cancer diagnosis. We also found 63 upstream regulators that can inhibit or activate the expression of the DEPs. Combining the proteomic and transcriptomic analyses revealed 12 common pathways. This study provides novel insights into H. pylori-associated GML. The DEPs we found may be good candidates for GML diagnosis and treatment. CONCLUSIONS This study revealed specific pathways related to GML and potential biomarkers for GML diagnosis.
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Prevalence of the Helicobacter pylori babA2 Gene in Children Mainly Depends on the PCR Primer Set Used. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2020; 2020:4080248. [PMID: 32855749 PMCID: PMC7443014 DOI: 10.1155/2020/4080248] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/20/2020] [Accepted: 07/28/2020] [Indexed: 02/07/2023]
Abstract
Various polymerase chain reaction- (PCR-) based methods with varying positivity rates were designed to detect the Helicobacter pylori babA2 gene. To compare different primer sets, babA2 prevalence was determined in 279 H. pylori-positive pediatric samples using the 832 bp, 139 bp, and 271 bp PCR primer sets, resulting in 34.0%, 51.3%, and 79.6% prevalence of the babA2 gene, respectively. The babA2 status determined using the 832 bp and 139 bp PCR primer sets significantly correlated with bacterial density and activity of inflammation, whereas no such correlations were found using the 271 bp PCR primer set. The 139 and 832 bp PCR primer sets concordantly detected the babA2 gene in 93 cases; however, in comparison to the 832 bp PCR primer set, the 139 bp PCR primer set detected additional 50 babA2 cases, whereas only two 832 bp positive cases were missed. The 271 bp PCR primer set missed 32 babA2 cases that were 832 bp and/or 139 bp PCR positive, but tested solely positive in 109 cases. Interestingly, cloning of a subset of 271 bp PCR positive samples revealed amplification of the babA/B gene chimera. Hence, in our opinion, the 271 bp PCR protocol is not a reliable diagnostic tool for detecting the babA2 gene in children. Our results reaffirm previous observations that the use of certain babA2 PCR primer sets can significantly impact estimation of the prevalence and clinical relevance of the H. pylori babA2 gene in children, suggesting babA2 detection methods should be carefully selected.
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Hanafiah A, Lopes BS. Genetic diversity and virulence characteristics of Helicobacter pylori isolates in different human ethnic groups. INFECTION GENETICS AND EVOLUTION 2019; 78:104135. [PMID: 31837482 DOI: 10.1016/j.meegid.2019.104135] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 12/03/2019] [Accepted: 12/06/2019] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori is the most predominant bacterium in almost 50% of the world's population and colonization causes a persistent inflammatory response leading to chronic gastritis. It shows high genetic diversity and individuals generally harbour a distinct bacterial population. With the advancement of whole-genome sequencing technology, new H. pylori subpopulations have been identified that show admixture between various H. pylori strains. Genotypic variation of H. pylori may be related to the presence of virulence factors among strains and is associated with different outcomes of infection in different individuals. This review summarizes the genetic diversity in H. pylori strain populations and its virulence characteristics responsible for variable outcomes in different ethnic groups.
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Affiliation(s)
- Alfizah Hanafiah
- Department of Medical Microbiology & Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000 Cheras, Kuala Lumpur, Malaysia.
| | - Bruno S Lopes
- Department of Medical Microbiology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, 0:025 Polwarth Building, Aberdeen AB25 2ZD, United Kingdom.
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The Prevalence of Helicobacter Pylori babA, homB, aspA, and sabA Genes and Its Relationship with Clinical Outcomes in Turkey. Can J Gastroenterol Hepatol 2019; 2019:1271872. [PMID: 31312620 PMCID: PMC6595381 DOI: 10.1155/2019/1271872] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 05/23/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS The cag A and vac A genes of Helicobacter pylori (H. pylori) are closely associated with the pathogenicity of bacteria. However, the significance of H. pylori babA, homB, aspA, and sabA genes is not clear in phenotypic characteristics of virulence. This study aimed to investigate the frequency and importance of these genes in patients with H. pylori positive peptic ulcer (PU). MATERIALS AND METHODS Patients with a PU or nonulcer dyspepsia (NUD) based on the upper gastrointestinal (UGI) endoscopy findings were included in the study. Biopsy samples from antrum and corpus were cultured into Columbia agar. H pylori were characterized by urease, catalase, oxidase test, and gram staining. Genomic DNA was extracted and stored. The babA, homB, aspA, and sabA genes were determined by using polymerase chain reaction analysis. RESULTS A total 214 patients were included (99 PU and 115 NUD) and H. pylori could be isolated in 82 patients (36 PU and 46 NUD). The frequency of the babA (25% vs. 15.2%, p=0.25), homB (2.7% vs. 4.3%, p=1), aspA (69.4% vs. 73.9%, p=0.2), and sabA (2.7% vs. 10.8%, p=0.88) genotypes was not different between PU and NUD patients. There were some correlations between the presences of these genes. CONCLUSION This study managed to determine babA, homB, aspA, and sabA genes of H. pylori by PCR. However, the frequency of these factors was not different in patients with PU and NUD. There is no role of babA, homB, aspA, and sabA genes for the development of peptic ulcer in Turkish population.
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Gonciarz W, Walencka M, Moran AP, Hinc K, Obuchowski M, Chmiela M. Upregulation of MUC5AC production and deposition of LEWIS determinants by HELICOBACTER PYLORI facilitate gastric tissue colonization and the maintenance of infection. J Biomed Sci 2019; 26:23. [PMID: 30841890 PMCID: PMC6402143 DOI: 10.1186/s12929-019-0515-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 02/19/2019] [Indexed: 02/07/2023] Open
Abstract
Background Helicobacter pylori bacteria colonize human gastric mucosa, cause chronic inflammation, peptic ulcers and gastric cancer. Colonization is mediated by H. pylori adhesins, which preferentially bind mucin 5 (MUC5AC) and Lewis (Le) determinants. The aim of this study was to evaluate the influence of H. pylori and their components on MUC5AC production and deposition of LeX/LeY in gastric epithelial cells in relation to bacterial adhesion using Caviae porcellus primary gastric epithelial cells and an in vivo model of experimental H. pylori infection in these animals. Methods MUCA5C and LeX/LeY were induced in vitro by live H. pylori reference strain CCUG 17874 (2 × 107 CFU/ml), H. pylori glycine acid extract (GE), 10 μg/ml; cytotoxin associated gene A (CagA) protein, 1 μl/ml; UreA urease subunit, 5 μg/ml; lipopolysaccharide (LPS) 25 ng/ml and imaged by fluorescence microscopy after anti-MUC5AC or anti-LeX/LeY FITC antibody staining. Bacterial adhesion was imaged by using anti-H. pylori FITC antibodies. The animals were inoculated per os with H. pylori (3 times in 2 days intervals, 1 × 1010 CFU/ml). After 7 or 28 days an infection and inflammation were assessed by histological, serological and molecular methods. Gastric tissue sections of infected and control animals were screend for MUCA5C and LeX, and H. pylori adhesion as above. Results MUC5AC production and deposition of Lewis determinants, especially LeX were upregulated in the milieu of live H. pylori as well as GE, CagA, UreA or LPS in vitro and in vivo during infection, more effectively in the acute (7 days) than in the chronic (28 days) phase of infection. This was related to enhanced adhesion of H. pylori, which was abrogated by anti-MUC5AC and anti-LeX or anti-LeY antibody treatment. Conclusions Modulation of MUCA5C production and LeX/LeY deposition in the gastric mucosa by H. pylori can significantly increase gastric tissue colonization during H. pylori infection.
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Affiliation(s)
- Weronika Gonciarz
- Division of Gastroimmunology, Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Łódź, Banacha 12/16, 90-237, Łódź, Poland
| | - Maria Walencka
- Division of Gastroimmunology, Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Łódź, Banacha 12/16, 90-237, Łódź, Poland
| | - Anthony P Moran
- Department of Microbiology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland
| | - Krzysztof Hinc
- Laboratory of Molecular Bacteriology, Intercollegiate Faculty of Biotechnology UG-MUG, Medical University of Gdańsk, 80-210, Gdańsk, Poland
| | - Michał Obuchowski
- Laboratory of Molecular Bacteriology, Intercollegiate Faculty of Biotechnology UG-MUG, Medical University of Gdańsk, 80-210, Gdańsk, Poland
| | - Magdalena Chmiela
- Division of Gastroimmunology, Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Łódź, Banacha 12/16, 90-237, Łódź, Poland.
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Genetic Polymorphisms in Inflammatory and Other Regulators in Gastric Cancer: Risks and Clinical Consequences. Curr Top Microbiol Immunol 2019; 421:53-76. [PMID: 31123885 DOI: 10.1007/978-3-030-15138-6_3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Helicobacter pylori infection is associated with the development of a chronic inflammatory response, which may induce peptic ulcers, gastric cancer (GC), and mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic H. pylori infection promotes the genetic instability of gastric epithelial cells and interferes with the DNA repair systems in host cells. Colonization of the stomach with H. pylori is an important cause of non-cardia GC and gastric MALT lymphoma. The reduction of GC development in patients who underwent anti-H. pylori eradication schemes has also been well described. Individual susceptibility to GC development depends on the host's genetic predisposition, H. pylori virulence factors, environmental conditions, and geographical determinants. Biological determinants are urgently sought to predict the clinical course of infection in individuals with confirmed H. pylori infection. Possible candidates for such biomarkers include genetic aberrations such as single-nucleotide polymorphisms (SNPs) found in various cytokines/growth factors (e.g., IL-1β, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A/B, IFN-γ, TNF, TGF-β) and their receptors (IL-RN, TGFR), innate immunity receptors (TLR2, TLR4, CD14, NOD1, NOD2), enzymes involved in signal transduction cascades (PLCE1, PKLR, PRKAA1) as well as glycoproteins (MUC1, PSCA), and DNA repair enzymes (ERCC2, XRCC1, XRCC3). Bacterial determinants related to GC development include infection with CagA-positive (particularly with a high number of EPIYA-C phosphorylation motifs) and VacA-positive isolates (in particular s1/m1 allele strains). The combined genotyping of bacterial and host determinants suggests that the accumulation of polymorphisms favoring host and bacterial features increases the risk for precancerous and cancerous lesions in patients.
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Carbohydrate-Dependent and Antimicrobial Peptide Defence Mechanisms Against Helicobacter pylori Infections. Curr Top Microbiol Immunol 2019; 421:179-207. [PMID: 31123890 DOI: 10.1007/978-3-030-15138-6_8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The human stomach is a harsh and fluctuating environment for bacteria with hazards such as gastric acid and flow through of gastric contents into the intestine. H. pylori gains admission to a stable niche with nutrient access from exudates when attached to the epithelial cells under the mucus layer, whereof adherence to glycolipids and other factors provides stable and intimate attachment. To reach this niche, H. pylori must overcome mucosal defence mechanisms including the continuously secreted mucus layer, which provides several layers of defence: (1) mucins in the mucus layer can bind H. pylori and transport it away from the gastric niche with the gastric emptying, (2) mucins can inhibit H. pylori growth, both via glycans that can have antibiotic like function and via an aggregation-dependent mechanism, (3) antimicrobial peptides (AMPs) have antimicrobial activity and are retained in a strategic position in the mucus layer and (4) underneath the mucus layer, the membrane-bound mucins provide a second barrier, and can function as releasable decoys. Many of these functions are dependent on H. pylori interactions with host glycan structures, and both the host glycosylation and concentration of antimicrobial peptides change with infection and inflammation, making these interactions dynamic. Here, we review our current understanding of mucin glycan and antimicrobial peptide-dependent host defence mechanisms against H. pylori infection.
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Chang WL, Yeh YC, Sheu BS. The impacts of H. pylori virulence factors on the development of gastroduodenal diseases. J Biomed Sci 2018; 25:68. [PMID: 30205817 PMCID: PMC6131906 DOI: 10.1186/s12929-018-0466-9] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 08/21/2018] [Indexed: 12/12/2022] Open
Abstract
Although most H. pylori infectors are asymptomatic, some may develop serious disease, such as gastric adenocarcinoma, gastric high-grade B cell lymphoma and peptic ulcer disease. Epidemiological and basic studies have provided evidence that infection with H. pylori carrying specific virulence factors can lead to more severe outcome. The virulence factors that are associated with gastric adenocarcinoma development include the presence, expression intensity and types of cytotoxin-associated gene A (CagA, especially EPIYA-D type and multiple copies of EPIYA-C) and type IV secretion system (CagL polymorphism) responsible for its translocation into the host cells, the genotypes of vacuolating cytotoxin A (vacA, s1/i1/m1 type), and expression intensity of blood group antigen binding adhesin (BabA, low-producer or chimeric with BabB). The presence of CagA is also related to gastric high-grade B cell lymphoma occurrence. Peptic ulcer disease is closely associated with cagA-genopositive, vacA s1/m1 genotype, babA2-genopositive (encodes BabA protein), presence of duodenal ulcer promoting gene cluster (dupA cluster) and induced by contact with epithelium gene A1 (iceA1), and expression status of outer inflammatory protein (OipA). The prevalence of these virulence factors is diverse among H. pylori isolated from different geographic areas and ethnic groups, which may explain the differences in disease incidences. For example, in East Asia where gastric cancer incidence is highest worldwide, almost all H. pylori isolates were cagA genopositive, vacA s1/i1/m1 and BabA-expressing. Therefore, selection of appropriate virulence markers and testing methods are important when using them to determine risk of diseases. This review summarizes the evidences of H. pylori virulence factors in relation with gastroduodenal diseases and discusses the geographic differences and appropriate methods of analyzing these virulence markers.
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Affiliation(s)
- Wei-Lun Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan, Taiwan
| | - Yi-Chun Yeh
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan, Taiwan
| | - Bor-Shyang Sheu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan, Taiwan. .,Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan.
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Šterbenc A, Poljak M, Zidar N, Luzar B, Homan M. Prevalence of the Helicobacter pylori homA and homB genes and their correlation with histological parameters in children. Microb Pathog 2018; 125:26-32. [PMID: 30195645 DOI: 10.1016/j.micpath.2018.09.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 09/03/2018] [Accepted: 09/05/2018] [Indexed: 12/16/2022]
Abstract
The significance of Helicobacter pylori (H. pylori) virulence genes such as cagA and vacA has been extensively studied in children; however, data regarding the significance of homA and homB genes are scarce. The aim of our study was to evaluate the prevalence and clinical relevance of these genes in Slovenian children. All children diagnosed with H. pylori infection between 1993 and 2013 were included in the study (n = 343). DNA was extracted from biopsy specimens previously used for the rapid urease test. Five histological parameters were evaluated and the presence of the vacA, cagA, iceA, babA2, and homA and homB genes was determined by PCR amplification. The homA and homB genes were detected in 174/285 (61.1%) and 116/285 (40.7%) strains, respectively. The presence of the homA gene was significantly associated with the absence of the homB gene (P < 0.001); however, no associations were found between the presence of either the homA or homB genes and any of the other investigated virulence genes. Similarly, there were no correlations between the presence of the homA and homB genes and any of the histological parameters. In contrast, genotype profiles vacA s1m1/cagA+/babA2+/homB+, vacA s1m2/cagA+/babA2+/homA+, vacA s1m1/cagA+/babA2+/homA+, vacA s1m1/cagA+/babA2-/homA+, vacA s1m2/cagA-/babA2-/homA+, and vacA s2m2/cagA-/babA2-/homB+ were associated with a higher degree of gastric mucosal damage. Thus, although the homA and homB genes did not represent important individual virulence markers in this population, they may act synergistically with other H. pylori virulence genes, causing severe gastritis in children.
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Affiliation(s)
- Anja Šterbenc
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Mario Poljak
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nina Zidar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Boštjan Luzar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Matjaž Homan
- Department of Gastroenterology, Hepatology, and Nutrition, University Children's Hospital, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
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Ansari S, Kabamba ET, Shrestha PK, Aftab H, Myint T, Tshering L, Sharma RP, Ni N, Aye TT, Subsomwong P, Uchida T, Ratanachu-ek T, Vilaichone RK, Mahachai V, Matsumoto T, Akada J, Yamaoka Y. Helicobacter pylori bab characterization in clinical isolates from Bhutan, Myanmar, Nepal and Bangladesh. PLoS One 2017; 12:e0187225. [PMID: 29107979 PMCID: PMC5673166 DOI: 10.1371/journal.pone.0187225] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 10/16/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Helicobacter pylori BabA is an important outer membrane protein that involves in the attachment to the gastric mucosa and enhances the virulence property of the bacterium. This study was aimed to characterize the bab genotypes, to evaluate its association with cagA, vacA and clinical diseases as well as degree of gastric inflammation. METHODS H. pylori isolates from four countries were subjected for the characterization of bab. The locus specific forward and bab specific reverse primers were used to get the specific products by PCR, which could distinguish the three locus (A, B and C). The histological activities were evaluated according to the Updated Sydney system. RESULT In patients from high risk countries (Bhutan and Myanmar) relatively higher frequencies of strains with babA-positivity (91.8% and 90.7%, respectively), babA at locus A (98% and 91.2%, respectively) and with single babA (96.8% and 91.2%, respectively) were found. Strains with two loci occupied were the most prevalent in Bhutan (84.6%), Myanmar (74.7%), Nepal (58.3%) and Bangladesh (56.9%). The genotype babA at locus A/babB at locus B/bab-negative at locus C (babA/babB/-) was the most common genotype isolated from Bhutan (82.7%), Myanmar (58.7%), Nepal (32%) and Bangladesh (31.4%) among all genotypes assessed. This genotype was also associated with the peptic ulcer disease (P = 0.013) when compared to gastritis. babA-positive characteristics and the genotype babA/babB/- exhibited the enhanced histological activities. CONCLUSIONS The higher prevalence of virulence associated babA-positive characteristics and enhanced histological activities in Bhutan than in Myanmar, Nepal and Bangladesh might partly explain why the peoples in Bhutan are at higher risk for developing severe gastric complications.
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Affiliation(s)
- Shamshul Ansari
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
| | | | - Pradeep Krishna Shrestha
- Gastroenterology Department, Maharajgunj Medical Campus, Tribhuvan University Teaching Hospital, Kathmandu, Nepal
| | - Hafeza Aftab
- Department of Gastroenterology, Dhaka Medical College and Hospital, Dhaka, Bangladesh
| | - Thein Myint
- Department of Gastroenterology, Yangon General Hospital, Yangon, Myanmar
| | - Lotay Tshering
- Department of Surgery, Jigme Dorji Wangchuck National Referral Hospital, Thimphu, Bhutan
| | - Rabi Prakash Sharma
- Gastroenterology Department, Maharajgunj Medical Campus, Tribhuvan University Teaching Hospital, Kathmandu, Nepal
| | - Nwe Ni
- Department of Gastroenterology, Mandalay General Hospital and University of Medicine (Mandalay), Mandalay, Myanmar
| | - Than Than Aye
- Department of Gastroenterology, Thingangyun Sanpya General Hospital and University of Medicine (2), Thingangyun, Myanmar
| | - Phawinee Subsomwong
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
| | - Tomohisa Uchida
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Hasama-machi, Yufu-City, Oita, Japan
| | | | - Ratha-korn Vilaichone
- Gastroenterology Unit, Department of Medicine, Thammasat University Hospital, Pathum Thani, Thailand
| | | | - Takashi Matsumoto
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
| | - Junko Akada
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
- Department of Medicine-Gastroenterology, Baylor College of Medicine, Houston, TX, United States of America
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Histo-blood group carbohydrates as facilitators for infection by Helicobacter pylori. INFECTION GENETICS AND EVOLUTION 2017; 53:167-174. [DOI: 10.1016/j.meegid.2017.05.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 05/06/2017] [Accepted: 05/30/2017] [Indexed: 02/07/2023]
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Ansari S, Yamaoka Y. Helicobacter pylori BabA in adaptation for gastric colonization. World J Gastroenterol 2017; 23:4158-4169. [PMID: 28694656 PMCID: PMC5483490 DOI: 10.3748/wjg.v23.i23.4158] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/12/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) as a causative agent of gastric complications, is well adapted for the colonization of gastric mucosa. Although the infectious process depends on several factors, the adhesion to the gastric mucosa is the first and important step. Among several outer membrane proteins, BabA is one of the significant protein involving in many inflammatory processes in addition to its role in the attachment for the persistent colonization. We performed a PubMed search using the key words: “babA”, “pylori”, “gastric complications”, “homologous recombination”, “slipped strand mispairing”; a total of 249 articles were displayed. Of these we mainly focused on articles with the full text in English and published between 2005 and 2016. H. pylori BabA is involved in binding with receptors; however, its synthesis is regulated by phase variation. In this review we confirm that H. pylori babA can be modulated at the molecular and functional levels to adapt to the stress within the gastro-intestinal tract.
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Floch P, Mégraud F, Lehours P. Helicobacter pylori Strains and Gastric MALT Lymphoma. Toxins (Basel) 2017; 9:toxins9040132. [PMID: 28397767 PMCID: PMC5408206 DOI: 10.3390/toxins9040132] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 03/27/2017] [Accepted: 04/03/2017] [Indexed: 02/07/2023] Open
Abstract
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.
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Affiliation(s)
- Pauline Floch
- INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France.
| | - Francis Mégraud
- INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France.
| | - Philippe Lehours
- INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France.
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BabA dependent binding of Helicobacter pylori to human gastric mucins cause aggregation that inhibits proliferation and is regulated via ArsS. Sci Rep 2017; 7:40656. [PMID: 28106125 PMCID: PMC5247751 DOI: 10.1038/srep40656] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 12/09/2016] [Indexed: 01/25/2023] Open
Abstract
Mucins in the gastric mucus layer carry a range of glycan structures, which vary between individuals, can have antimicrobial effect or act as ligands for Helicobacter pylori. Mucins from various individuals and disease states modulate H. pylori proliferation and adhesin gene expression differently. Here we investigate the relationship between adhesin mediated binding, aggregation, proliferation and adhesin gene expression using human gastric mucins and synthetic adhesin ligand conjugates. By combining measurements of optical density, bacterial metabolic activity and live/dead stains, we could distinguish bacterial aggregation from viability changes, enabling elucidation of mechanisms behind the anti-prolific effects that mucins can have. Binding of H. pylori to Leb-glycoconjugates inhibited the proliferation of the bacteria in a BabA dependent manner, similarly to the effect of mucins carrying Leb. Furthermore, deletion of arsS lead to a decrease in binding to Leb-glycoconjugates and Leb-decorated mucins, accompanied by decreased aggregation and absence of anti-prolific effect of mucins and Leb-glycoconjugates. Inhibition of proliferation caused by adhesin dependent binding to mucins, and the subsequent aggregation suggests a new role of mucins in the host defense against H. pylori. This aggregating trait of mucins may be useful to incorporate into the design of adhesin inhibitors and other disease intervention molecules.
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Chen YL, Mo XQ, Huang GR, Huang YQ, Xiao J, Zhao LJ, Wei HY, Liang Q. Gene polymorphisms of pathogenic Helicobacter pylori in patients with different types of gastrointestinal diseases. World J Gastroenterol 2016; 22:9718-9726. [PMID: 27956795 PMCID: PMC5124976 DOI: 10.3748/wjg.v22.i44.9718] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 08/17/2016] [Accepted: 09/06/2016] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a kind of chronic infectious pathogen which can cause chronic gastritis, peptic ulcer, gastric cancer and other diseases. The genetic structure of the pathogenic genes of H. pylori varies largely, which contributes to the differences in virulence among various strains, and in clinical symptoms. Virulence genes of H. pylori can be categorized into three main classes: those related to adhesion and colonization, those related to gastric mucosal injury, and others. This review focuses on the relationship between genetic polymorphisms of the three classes of virulence genes of H. pylori and diseases. Most of the genetic polymorphisms of the main virulence factors of H. pylori are summarized in this paper.
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Demiray-Gürbüz E, Yılmaz Ö, Olivares AZ, Gönen C, Sarıoğlu S, Soytürk M, Tümer S, Altungöz O, Şimşek İ, Perez Perez GI. Rapid identification of Helicobacter pylori and assessment of clarithromycin susceptibility from clinical specimens using FISH. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2016; 3:29-37. [PMID: 28138399 PMCID: PMC5259560 DOI: 10.1002/cjp2.57] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/03/2016] [Accepted: 08/12/2016] [Indexed: 12/21/2022]
Abstract
Helicobacter pylori remains one of the most common bacterial infections worldwide. Clarithromycin resistance is the most important cause of H. pylori eradication failures. Effective antibiotic therapies in H. pylori infection must be rapidly adapted to local resistance patterns. We investigated the prevalence of clarithromycin resistance due to mutations in positions 2142 and 2143 of 23SrRNA gene of H. pylori by fluorescence in situ hybridisation (FISH), and compared with culture and antimicrobial susceptibility testing in 234 adult patients with dyspepsia who were enrolled. Antrum and corpus biopsy specimens were obtained for rapid urease test, histopathology and culture. Epsilometer test was used to assess clarithromycin susceptibility. H. pylori presence and clarithromycin susceptibility were determined by FISH in paraffin‐embedded biopsy specimens. We found that 164 (70.1%) patients were positive for H. pylori based on clinical criteria, 114 (69.5% CI 62.5–76.6%) were culture positive, and 137 (83.5% CI 77.8–89.2%) were FISH positive. Thus the sensitivity of FISH was significantly superior to that of culture. However specificity was not significantly different (91.4 versus 100.0%, respectively). The resistance rate to clarithromycin for both antrum and corpus was detected in H. pylori‐positive patients; 20.2% by FISH and 28.0% by E‐test.The concordance between E‐test and FISH was only 89.5% due to the presence of point mutations different from A2143G, A2142G or A2142C. We conclude that FISH is significantly more sensitive than culture and the E‐test for the detection of H. pylori and for rapid determinination of claritromycin susceptibility. The superior hybridisation efficiency of FISH is becoming an emerging molecular tool as a reliable, rapid and sensitive method for the detection and visualisation of H. pylori, especially when the management of H. pylori eradication therapy is necessary. This is particularly important for the treatment of patients with H. pylori eradication failure.
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Affiliation(s)
- Ebru Demiray-Gürbüz
- Department of Medical Microbiology, Faculty of Medicine Dokuz Eylül University İzmir Turkey
| | - Özlem Yılmaz
- Department of Medical Microbiology, Faculty of Medicine Dokuz Eylül University İzmir Turkey
| | - Asalia Z Olivares
- Departments of Medicine and Microbiology New York University, School of Medicine, NYUSM New York NY USA
| | - Can Gönen
- Departments of Gastroenterology, Faculty of Medicine Dokuz Eylül University Izmir Turkey
| | - Sülen Sarıoğlu
- Pathology, Faculty of Medicine Dokuz Eylül University Izmir Turkey
| | - Müjde Soytürk
- Departments of Gastroenterology, Faculty of Medicine Dokuz Eylül University Izmir Turkey
| | - Sait Tümer
- Medical Biology and Genetics, Faculty of Medicine Dokuz Eylül University İzmir Türkiye
| | - Oğuz Altungöz
- Medical Biology and Genetics, Faculty of Medicine Dokuz Eylül University İzmir Türkiye
| | - İlkay Şimşek
- Departments of Gastroenterology, Faculty of Medicine Dokuz Eylül University Izmir Turkey
| | - Guillermo I Perez Perez
- Departments of Medicine and Microbiology New York University, School of Medicine, NYUSM New York NY USA
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Saberi S, Schmidt A, Eybpoosh S, Esmaili M, Talebkhan Y, Mohajerani N, Oghalaie A, Eshagh Hosseini M, Mohagheghi MA, Bugaytova J, Borén T, Mohammadi M. Helicobacter pylori Strains from Duodenal Ulcer Patients Exhibit Mixed babA/B Genotypes with Low Levels of BabA Adhesin and Lewis b Binding. Dig Dis Sci 2016; 61:2868-2877. [PMID: 27318698 DOI: 10.1007/s10620-016-4217-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 05/27/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND BabA is a Helicobacter pylori cell surface adhesin, which binds to the ABO/Le(b) histo-blood group antigens (Le(b)) and serves as a virulence factor. METHODS H. pylori single colonies were isolated from 156 [non-ulcer dyspepsia (NUD) = 97, duodenal ulcer (DU) = 34, gastric cancer (GC) = 25)] patients. babA and babB genes were evaluated by gene/locus-specific PCR. BabA protein expression and Le(b) binding activity were determined by immunoblotting and ELISA, respectively. RESULTS The combined categorization of H. pylori strains based on high, low or no levels of BabA expression and Le(b) binding, produced 4 groups: (I) BabA-high/Le(b)-high (36 %), (II) BabA-low/Le(b)-low (26 %), (III) BabA-neg/Le(b)-low (30 %) and (IV) BabA-neg/Le(b)-neg (8 %) strains. The majority (63 %) of the BabA-low/Le(b)-low strains exhibited mixed babA/B genotypes as compared to merely 18 % of the BabA-high/Le(b)-high, 15 % of the BabA-neg/Le(b)-neg and 11 % of the BabA-neg/Le(b)-low (P = 0.0001) strains. In contrast to NUD strains, the great majority (70 %) of DU strains were BabA-low/Le(b)-low (11 %, P = 0.0001), which compared to NUD strains, enhanced the risk of DU by 18.8-fold. In parallel, infection with babA/B mixed genotype strains amplified the risk of DU by 3.6-fold (vs. babA-positive: P = 0.01) to 6.9-fold (vs. babA-negative: P = 0.007). CONCLUSIONS Here, we show higher prevalence of mixed babA/B genotypes among BabA-low/Le(b)-low clinical strains. Recombination of babA and babB genes across their loci may yield lower BabA expression and lower Le(b) binding activity. We conclude that H. pylori strains with lower Le(b) binding activity are better adapted for colonization of the gastric metaplastic patches in the duodenum and enhance the risk of duodenal ulcers.
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Affiliation(s)
- Samaneh Saberi
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Alexej Schmidt
- Department of Medical Biosciences and Pathology, Umeå University, 901 85, Umeå, Sweden
| | - Sana Eybpoosh
- Research Center for Modeling in Health, Institute for Future Studies in Health, Kerman University of Medical Sciences, Kerman, 7618747653, Iran
| | - Maryam Esmaili
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Yeganeh Talebkhan
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Nazanin Mohajerani
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Akbar Oghalaie
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Mahmoud Eshagh Hosseini
- Department of Gastroenterology, Amiralam Hospital, Tehran University of Medical Sciences, Tehran, 1145765111, Iran
| | | | - Jeanna Bugaytova
- Department of Medical Biochemistry and Biophysics, Umeå University, 901 87, Umeå, Sweden
| | - Thomas Borén
- Department of Medical Biochemistry and Biophysics, Umeå University, 901 87, Umeå, Sweden.
| | - Marjan Mohammadi
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, 1316943551, Iran.
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Ghosh P, Sarkar A, Ganguly M, Raghwan, Alam J, De R, Mukhopadhyay AK. Helicobacter pylori strains harboring babA2 from Indian sub population are associated with increased virulence in ex vivo study. Gut Pathog 2016; 8:1. [PMID: 26759607 PMCID: PMC4709984 DOI: 10.1186/s13099-015-0083-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 12/23/2015] [Indexed: 12/13/2022] Open
Abstract
Background The babA2 gene along with the cagA and vacA of Helicobacter pylori has been considered as a risk factor for the disease outcome in certain populations. This study was aimed to understand the role of babA2 of H. pylori with the background of cagA and vacA in disease manifestations in Indian sub population. Methods A total of 114 H. pylori strains isolated from duodenal ulcer (DU) (n = 53) and non-ulcer dyspepsia (NUD) patients (n = 61) were
screened for the prevalence of these virulence markers by PCR. The comparative study of IL-8 production and apoptosis were done by co-culturing the AGS cell line with H. pylori strains with different genotypes. Adherence assay was performed with babA2 positive and negative strains. Two isogenic mutants of babA2 were constructed and the aforesaid comparative studies were carried out. Results PCR results indicated that 90.6 % (48/53), 82 % (50/61) and 73.6 % (39/53) strains from DU patients were positive for cagA, vacA, and babA2, respectively. Whereas the prevalence of these genes in NUD subjects were 70.5 % (43/61); 69.8 % (37/53), and 65.6 % (39/61), respectively. Although adherence to AGS cells was comparable among strains with babA2 positive and negative genotypes, but the triple positive strains could induce highest degree of IL-8 production and apoptosis, followed by the cagA−/vacA−/babA2+ strains and triple negative strains, respectively. The wild type strains showed significantly higher IL-8 induction as well as apoptosis in ex vivo than its isogenic mutant of babA2. Conclusion PCR study demonstrated that there was no significant association between the distribution of babA2 genotype or of triple positive strains and disease outcome in this sub population. The adherence assay showed that there was no significant difference in the extent of adherence to AGS cells among babA2 positive and negative strains. But the ex vivo study indicated that the triple positive or even the babA2 only positive strains are involved in increased virulence. The wild type strains also exhibited increased virulence compared to the babA2 mutant strains. This inconsistency demonstrated that bacterial genotype along with host genetic polymorphisms or other factors play important role in determining the clinical manifestation of H. pylori infections.
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Affiliation(s)
- Prachetash Ghosh
- Division of Bacteriology, National Institute of Cholera & Enteric Diseases, P 33, CIT Road, Scheme XM, Beliaghata, Kolkata, 700010 India
| | - Avijit Sarkar
- Division of Bacteriology, National Institute of Cholera & Enteric Diseases, P 33, CIT Road, Scheme XM, Beliaghata, Kolkata, 700010 India
| | - Mou Ganguly
- Division of Bacteriology, National Institute of Cholera & Enteric Diseases, P 33, CIT Road, Scheme XM, Beliaghata, Kolkata, 700010 India
| | - Raghwan
- Division of Bacteriology, National Institute of Cholera & Enteric Diseases, P 33, CIT Road, Scheme XM, Beliaghata, Kolkata, 700010 India
| | - Jawed Alam
- Division of Bacteriology, National Institute of Cholera & Enteric Diseases, P 33, CIT Road, Scheme XM, Beliaghata, Kolkata, 700010 India
| | - Ronita De
- Division of Bacteriology, National Institute of Cholera & Enteric Diseases, P 33, CIT Road, Scheme XM, Beliaghata, Kolkata, 700010 India
| | - Asish K Mukhopadhyay
- Division of Bacteriology, National Institute of Cholera & Enteric Diseases, P 33, CIT Road, Scheme XM, Beliaghata, Kolkata, 700010 India
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Glycan:glycan interactions: High affinity biomolecular interactions that can mediate binding of pathogenic bacteria to host cells. Proc Natl Acad Sci U S A 2015; 112:E7266-75. [PMID: 26676578 DOI: 10.1073/pnas.1421082112] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Cells from all domains of life express glycan structures attached to lipids and proteins on their surface, called glycoconjugates. Cell-to-cell contact mediated by glycan:glycan interactions have been considered to be low-affinity interactions that precede high-affinity protein-glycan or protein-protein interactions. In several pathogenic bacteria, truncation of surface glycans, lipooligosaccharide (LOS), or lipopolysaccharide (LPS) have been reported to significantly reduce bacterial adherence to host cells. Here, we show that the saccharide component of LOS/LPS have direct, high-affinity interactions with host glycans. Glycan microarrays reveal that LOS/LPS of four distinct bacterial pathogens bind to numerous host glycan structures. Surface plasmon resonance was used to determine the affinity of these interactions and revealed 66 high-affinity host-glycan:bacterial-glycan pairs with equilibrium dissociation constants (K(D)) ranging between 100 nM and 50 µM. These glycan:glycan affinity values are similar to those reported for lectins or antibodies with glycans. Cell assays demonstrated that glycan:glycan interaction-mediated bacterial adherence could be competitively inhibited by either host cell or bacterial glycans. This is the first report to our knowledge of high affinity glycan:glycan interactions between bacterial pathogens and the host. The discovery of large numbers of glycan:glycan interactions between a diverse range of structures suggests that these interactions may be important in all biological systems.
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Uotani T, Miftahussurur M, Yamaoka Y. Effect of bacterial and host factors on Helicobacter pylori eradication therapy. Expert Opin Ther Targets 2015; 19:1637-50. [PMID: 26245678 DOI: 10.1517/14728222.2015.1073261] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION A clearer understanding of the factors affecting the cure rate of Helicobacter pylori infection might lead to the development of novel prevention strategies and therapeutic targets. AREAS COVERED This review covers two important issues that affect the eradication of H. pylori: bacterial and host factors. Several virulence factors have been shown to be predictors for gastroduodenal diseases. Successful treatment of H. pylori infection also depends on host genetic factors such as CYP2C19 and IL-1B. The latest evidence on host genetic factors is discussed. EXPERT OPINION The authors identify three main targets for achieving effective eradication therapy. The first therapeutic target is to identify counter measures for antibiotic-resistant H. pylori strains. Thus, antibiotic susceptibility should be checked in all patients, ideally, before the start of eradication treatment. The second therapeutic target is the inhibition of acid suppression. Maintaining a high intragastric pH for 24 h increases the effectiveness of some antibiotics and the eradication effects for H. pylori. The third therapeutic target is to identify high-risk groups; the CYP2C19 and IL-1B polymorphisms are candidates for significant risk factors. A personalized medical approach will likely increase the cure rate of H. pylori infection.
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Affiliation(s)
- Takahiro Uotani
- a 1 Oita University Faculty of Medicine, Department of Environmental and Preventive Medicine , 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan +81 97 586 5740 ; +81 97 586 5749 ; .,b 2 Baylor College of Medicine and Michael DeBakey Veterans Affairs Medical Center, Department of Gastroenterology and Hepatology , Houston, TX 77030, USA
| | - Muhammad Miftahussurur
- a 1 Oita University Faculty of Medicine, Department of Environmental and Preventive Medicine , 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan +81 97 586 5740 ; +81 97 586 5749 ; .,c 3 Airlangga University, Institute of Tropical Disease , Surabaya 60115, Indonesia
| | - Yoshio Yamaoka
- a 1 Oita University Faculty of Medicine, Department of Environmental and Preventive Medicine , 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan +81 97 586 5740 ; +81 97 586 5749 ; .,b 2 Baylor College of Medicine and Michael DeBakey Veterans Affairs Medical Center, Department of Gastroenterology and Hepatology , Houston, TX 77030, USA
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Almeida N, Donato MM, Romãozinho JM, Luxo C, Cardoso O, Cipriano MA, Marinho C, Fernandes A, Sofia C. Correlation of Helicobacter pylori genotypes with gastric histopathology in the central region of a South-European country. Dig Dis Sci 2015; 60:74-85. [PMID: 25142169 DOI: 10.1007/s10620-014-3319-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 08/01/2014] [Indexed: 12/30/2022]
Abstract
BACKGROUND Outcome of Helicobacter pylori (H. pylori) infection results from interaction of multiple variables including host, environmental and bacterial-associated virulence factors. AIM This study aimed to investigate the correlation of cagA, cagE, vacA, iceA and babA2 genotypes with gastric histopathology and disease phenotype in the central region of a South-European country. METHODS This prospective study involved 148 infected patients (110 female; mean age 43.5 ± 13.4 years) submitted to endoscopy with corpus and antrum biopsies. H. pylori was cultured and DNA extracted from the isolates. Genotypes were determined by PCR. Histopathological features were graded according to the updated Sydney system and OLGA/OLGIM classification. Only patients with single H. pylori genotypes and complete histopathological results were included. RESULTS Antrum samples presented higher degrees of atrophy, intestinal metaplasia, chronic inflammation and neutrophil activity. Genotype distribution was as follows: cagA-31.8 %; cagE-45.9 %; vacA s1a-24.3 %; vacA s1b-19.6 %; vacA s1c-0.7 %; vacA s2-55.4 %; vacA m1-20.9 %; vacA m2-79.1 %; vacA s1m1-18.9 %; vacA s1m2-25.7 %; vacA s2m1-2 %; vacA s2m2-53.4 %; iceA1-33.8 %; iceA2-66.2 %; babA2-12.2 %. CagA genotype was significantly associated with higher degrees of intestinal metaplasia, neutrophil activity, chronic inflammation and OLGIM stages. BabA2 was linked with higher H. pylori density. Strains with vacA s1m1 or vacA s1m1 + cagA positive genotypes had a significant association with peptic ulcer and vacA s2m2 with iron-deficient anemia. CONCLUSIONS cagA, vacA s1m1 and babA2 genotypes are relatively rare in the central region of Portugal. cagA-positive strains are correlated with more severe histopathological modifications. This gene is commonly associated with vacA s1m1, and such isolates are frequently found in patients with peptic ulcer.
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Affiliation(s)
- Nuno Almeida
- Gastroenterology Department, Coimbra University Hospital Centre, Praceta Mota Pinto e Avenida Bissaya Barreto, 3000-075, Coimbra, Portugal,
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Yamaoka Y, Miftahussurur M. Helicobacter pylori virulence genes and host genetic polymorphisms as risk factors for peptic ulcer disease. Expert Rev Gastroenterol Hepatol 2015; 9:1535-47. [PMID: 26470920 PMCID: PMC5332543 DOI: 10.1586/17474124.2015.1095089] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Helicobacter pylori infection plays an important role in the pathogenesis of peptic ulcer disease (PUD). Several factors have been proposed as possible H. pylori virulence determinants; for example, bacterial adhesins and gastric inflammation factors are associated with an increased risk of PUD. However, differences in bacterial virulence factors alone cannot explain the opposite ends of the PUD disease spectrum, that is duodenal and gastric ulcers; presumably, both bacterial and host factors contribute to the differential response. Carriers of the high-producer alleles of the pro-inflammatory cytokines IL-1B, IL-6, IL-8, IL-10, and TNF-α who also carry low-producer allele of anti-inflammatory cytokines have severe gastric mucosal inflammation, whereas carriers of the alternative alleles have mild inflammation. Recent reports have suggested that the PSCA and CYP2C19 ultra-rapid metabolizer genotypes are also associated with PUD.
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Affiliation(s)
- Yoshio Yamaoka
- Oita University, Baylor College of Medicine Houston United States
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Genetic battle between Helicobacter pylori and humans. The mechanism underlying homologous recombination in bacteria, which can infect human cells. Microbes Infect 2014; 16:833-9. [DOI: 10.1016/j.micinf.2014.08.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 07/01/2014] [Accepted: 08/04/2014] [Indexed: 12/20/2022]
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Homan M, Šterbenc A, Kocjan BJ, Luzar B, Zidar N, Orel R, Poljak M. Prevalence of the Helicobacter pylori babA2 gene and correlation with the degree of gastritis in infected Slovenian children. Antonie Van Leeuwenhoek 2014; 106:637-645. [PMID: 25055876 DOI: 10.1007/s10482-014-0234-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 07/07/2014] [Indexed: 12/16/2022]
Abstract
The aims of our study were to determine the prevalence of the babA2 gene within Helicobacter pylori strains circulating in the Slovenian pediatric population, to further clarify its significance in causing inflammation of gastric mucosa in children and to verify whether cagA, vacA, iceA and babA genes work independently or synergistically in causing gastritis. A total of 163 H. pylori isolates obtained from the same number of children were tested for the presence of cagA, vacA and iceA genes using previously established methods, while the babA2 gene was determined using novel polymerase chain reaction assay targeting a 139-bp fragment of the central region of babA2. The babA2 gene was detected in 47.9% of H. pylori samples. The presence of the babA2 gene was strongly associated with cagA, vacA s1 and vacA m1 genotype. The babA2 status correlated positively with bacterial density score, activity of inflammation and chronic inflammation of gastric mucosa. No significant correlation was found between the babA2 status and the presence of atrophy or intestinal metaplasia. In addition, the activity of gastric inflammation and density score were significantly associated with the coexpression of the cagA, vacA s1, vacA m1 and babA2 genes. The study, which included the largest number of pediatric H. pylori samples to date, confirmed that babA2 gene plays an important role in the pathogenesis of H. pylori gastritis in children. Furthermore, our results suggest that babA2, cagA and vacA s1 and m1 gene products may work synergistically in worsening the inflammation of gastric mucosa.
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Affiliation(s)
- Matjaž Homan
- Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital, Ljubljana, Slovenia,
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He C, Chen M, Liu J, Yuan Y. Host genetic factors respond to pathogenic step-specific virulence factors of Helicobacter pylori in gastric carcinogenesis. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2014; 759:14-26. [PMID: 24076409 DOI: 10.1016/j.mrrev.2013.09.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 09/13/2013] [Accepted: 09/13/2013] [Indexed: 12/18/2022]
Abstract
The interindividual differences in risk of Helicobacter pylori (H. pylori)-associated gastric cancer involve significant heterogeneities of both host genetics and H. pylori strains. Several recent studies proposed a distinct sequence for H. pylori exerting its virulence in the host stomach: (i) adhering to and colonizing the surface of gastric epithelial cells, (ii) evading and attenuating the host defense, and (iii) invading and damaging the gastric mucosa. This review focuses on several key issues that still need to be clarified, such as which virulence factors of H. pylori are involved in the three pathogenic steps, which host genes respond to the step-specific virulence factors, and whether and/or how the corresponding host genetic variations influence the risk of gastric carcinogenesis. Urease, BabA and SabA in the adhesion-step, PGN and LPS in the immune evasion-step, and CagA, VacA and Tipα in the mucosal damage-step were documented to play an important role in step-specific pathogenicity of H. pylori infection. There is evidence further supporting a role of potentially functional polymorphisms of host genes directly responding to these pathogenic step-specific virulence factors in the susceptibility of gastric carcinogenesis, especially for urease-interacting HLA class II genes, BabA-interacting MUC1, PGN-interacting NOD1, LPS-interacting TLR4, and CagA-interacting PTPN11 and CDH1. With the continuous improvement of understanding the genetic profile of H. pylori-associated gastric carcinogenesis, a person at increased risk for gastric cancer may benefit from several aspects of efforts: (i) prevent H. pylori infection with a vaccine targeting certain step-specific virulence factor; (ii) eradicate H. pylori infection by blocking step-specific psychopathological characteristics of virulence factors; and (iii) adjust host physiological function to resist the carcinogenic role of step-specific virulence factors or interrupt the cellular signal transduction of the interplay between H. pylori and host in each pathogenic step, especially for the subjects with precancerous lesions in the stomach.
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Affiliation(s)
- Caiyun He
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Moye Chen
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Jingwei Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China.
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Day CJ, Tram G, Hartley-Tassell LE, Tiralongo J, Korolik V. Assessment of glycan interactions of clinical and avian isolates of Campylobacter jejuni. BMC Microbiol 2013; 13:228. [PMID: 24119179 PMCID: PMC3852789 DOI: 10.1186/1471-2180-13-228] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 09/27/2013] [Indexed: 03/08/2023] Open
Abstract
BACKGROUND Campylobacter jejuni strain 11168 was demonstrated to have a broad specificity for eukaryotic surface glycosylation using glycan array analysis. The initial screen indicated that sialic acid and mannose are important binding partners after environmental stress, while galactose and fucose structures are likely to be involved in persistent infection. RESULTS In this broader study, five additional human/clinical isolates and six chicken isolates were fully assessed to determine their glycan binding capacity using an extended glycan array. C. jejuni 11168 was rescreened here due to the presence of glycoaminoglycan (GAG) and other structures that were not available on our previous glycan array. The current array analysis of additional C. jejuni strains confirmed the growth condition dependent differences in glycan binding that was previously observed for C. jejuni 11168. We noted strain to strain variations, particularly for the human isolates C. jejuni 520 and 81116 and the chicken isolate C. jejuni 331, with the majority of differences observed in galactose, mannose and GAG binding. Chicken isolates were found to bind to a broader range of glycans compared to the human isolates, recognising branched mannose and carageenan (red seaweed) glycans. Glycan array data was confirmed using cell-based lectin inhibition assays with the fucose (UEA-I) and mannose (ConA) binding lectins. CONCLUSIONS This study confirms that all C. jejuni strains tested bind to a broad range of glycans, with the majority of strains (all except 81116) altering recognition of sialic acid and mannose after environmental stress. Galactose and fucose structures were bound best by all strains when C. jejuni was grown under host like conditions confirming the likelihood of these structures being involved in persistent infection.
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Affiliation(s)
- Christopher J Day
- Institute for Glycomics, G26, Griffith University Gold Coast Campus, Queensland 4222, Australia.
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Posselt G, Backert S, Wessler S. The functional interplay of Helicobacter pylori factors with gastric epithelial cells induces a multi-step process in pathogenesis. Cell Commun Signal 2013; 11:77. [PMID: 24099599 PMCID: PMC3851490 DOI: 10.1186/1478-811x-11-77] [Citation(s) in RCA: 151] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 10/01/2013] [Indexed: 12/16/2022] Open
Abstract
Infections with the human pathogen Helicobacter pylori (H. pylori) can lead to severe gastric diseases ranging from chronic gastritis and ulceration to neoplastic changes in the stomach. Development and progress of H. pylori-associated disorders are determined by multifarious bacterial factors. Many of them interact directly with host cells or require specific receptors, while others enter the host cytoplasm to derail cellular functions. Several adhesins (e.g. BabA, SabA, AlpA/B, or OipA) establish close contact with the gastric epithelium as an important first step in persistent colonization. Soluble H. pylori factors (e.g. urease, VacA, or HtrA) have been suggested to alter cell survival and intercellular adhesions. Via a type IV secretion system (T4SS), H. pylori also translocates the effector cytotoxin-associated gene A (CagA) and peptidoglycan directly into the host cytoplasm, where cancer- and inflammation-associated signal transduction pathways can be deregulated. Through these manifold possibilities of interaction with host cells, H. pylori interferes with the complex signal transduction networks in its host and mediates a multi-step pathogenesis.
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Affiliation(s)
- Gernot Posselt
- Division of Molecular Biology, Department of Microbiology, Paris-Lodron University, Salzburg, Austria.
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Institut Pasteur Minisymposium on Bacterial Membranes 2013. Res Microbiol 2013. [DOI: 10.1016/j.resmic.2013.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Vaziri F, Peerayeh SN, Alebouyeh M, Mirzaei T, Yamaoka Y, Molaei M, Maghsoudi N, Zali MR. Diversity of Helicobacter pylori genotypes in Iranian patients with different gastroduodenal disorders. World J Gastroenterol 2013; 19:5685-5692. [PMID: 24039362 PMCID: PMC3769906 DOI: 10.3748/wjg.v19.i34.5685] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2012] [Revised: 09/11/2012] [Accepted: 11/14/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the diversity of Helicobacter pylori (H. pylori) genotypes and correlations with disease outcomes in an Iranian population with different gastroduodenal disorders. METHODS Isolates of H. pylori from patients with different gastroduodenal disorders were analyzed after culture and identification by phenotypic and genotypic methods. Genomic DNA was extracted with the QIAamp DNA mini kit (Qiagen, Germany). After DNA extraction, genotyping was done for cagA, vacA (s and m regions), iceA (iceA1 , iceA2 ) and babA with specific primers for each allele using polymerase chain reaction (PCR). All patients' pathologic and clinical data and their relation with known genotypes were analyzed by using SPSS version 19.0 software. χ² test and Fisher's exact test were used to assess relationships between categorical variables. The level of statistical significance was set at P < 0.05. RESULTS A total of 71 isolates from 177 patients with different gastroduodenal disorders were obtained. Based on analysis of the cagA gene (positive or negative), vacA s-region (s1 or s2), vacA m-region (m1 or m2), iceA allelic type (iceA1 and iceA2 ) and babA gene (positive or negative), twenty different genotypic combinations were recognized. The prevalence of cagA, vacA s1 , vacA s2 , vacA m1 , vacA m2 , iceA1 , iceA2 , iceA1+iceA2 and babA were 62%, 78.9%, 19.7%, 21.1%, 78.9%, 15.5%, 22.5%, 40.8% and 95.8%, respectively. Interestingly, evaluation of PCR results for cagA in 6 patients showed simultaneous existence of cagA variants according to their size diversities that proposed mixed infection in these patients. The most prevalent genotype in cagA-positive isolates was cagA⁺/vacAs1m2 /iceA1 +A2 /babA+ and in cagA-negative isolates was cagA⁻/vacAs1m2 /iceA-/babA+. There were no relationships between the studied genes and histopathological findings (H. pylori density, neutrophil activity, lymphoid aggregation in lamina propria and glandular atrophy). The strains which carry cagA, vacAs1/m1 , iceA2 and babA genes showed significant associations with severe active chronic gastritis (P = 0.011, 0.025, 0.020 and 0.031, respectively). The vacAs1 genotype had significant correlation with the presence of the cagA gene (P = 0.013). Also, babA genotype showed associations with cagA (P = 0.024). In the combined genotypes, only cagA⁺/vacAs1m1 /iceA2 /babA+ genotype showed correlation with severe active chronic gastritis (P = 0.025). CONCLUSION This genotyping panel can be a useful tool for detection of virulent H. pylori isolates and can provide valuable guidance for prediction of the clinical outcomes.
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The Role of Helicobacter pylori Outer Membrane Proteins in Adherence and Pathogenesis. BIOLOGY 2013; 2:1110-34. [PMID: 24833057 PMCID: PMC3960876 DOI: 10.3390/biology2031110] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 07/26/2013] [Accepted: 08/13/2013] [Indexed: 12/12/2022]
Abstract
Helicobacter pylori is one of the most successful human pathogens, which colonizes the mucus layer of the gastric epithelium of more than 50% of the world’s population. This curved, microaerophilic, Gram-negative bacterium induces a chronic active gastritis, often asymptomatic, in all infected individuals. In some cases, this gastritis evolves to more severe diseases such as peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. H. pylori has developed a unique set of factors, actively supporting its successful survival and persistence in its natural hostile ecological niche, the human stomach, throughout the individual’s life, unless treated. In the human stomach, the vast majority of H. pylori cells are motile in the mucus layer lining, but a small percentage adheres to the epithelial cell surfaces. Adherence to the gastric epithelium is important for the ability of H. pylori to cause disease because this intimate attachment facilitates: (1) colonization and persistence, by preventing the bacteria from being eliminated from the stomach, by mucus turnover and gastric peristalsis; (2) evasion from the human immune system and (3) efficient delivery of proteins into the gastric cell, such as the CagA oncoprotein. Therefore, bacteria with better adherence properties colonize the host at higher densities. H. pylori is one of the most genetically diverse bacterial species known and is equipped with an extraordinarily large set of outer membrane proteins, whose role in the infection and persistence process will be discussed in this review, as well as the different receptor structures that have been so far described for mucosal adherence.
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