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1
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Tamanna T, Rahman MS. Leveraging immunoinformatics for developing a multi-epitope subunit vaccine against Helicobacter pylori and Fusobacterium nucleatum. J Biomol Struct Dyn 2025; 43:1552-1565. [PMID: 38116749 DOI: 10.1080/07391102.2023.2292295] [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: 03/22/2023] [Accepted: 11/25/2023] [Indexed: 12/21/2023]
Abstract
Gastric ulcers caused by Helicobacter pylori and Fusobacterium nucleatum remain a significant global health concern without an established vaccine. In this study, we utilized immunoinformatics methods to design a multi-epitope vaccine targeting these pathogens. Outer membrane proteins from H. pylori and F. nucleatum were scrutinized to identify high antigenic T-cell and B-cell epitopes. The resulting vaccine comprised carefully analyzed and evaluated epitopes, including cytotoxic T-lymphocytes, helper T-lymphocytes, and linear B-lymphocytes epitopes. This vaccine exhibited notable antigenicity, suitable immunogenicity, and demonstrated non-allergenicity and non-toxicity. It displayed favorable physiochemical characteristics and high solubility. In interaction studies, the vaccine exhibited robust binding to toll-like receptor 4 (TLR4). Molecular dynamic simulations revealed cohesive structural integrity and stable attachment. Codon adaptation utilizing Escherichia coli K12 host yielded a vaccine with elevated Codon Adaptation Index (CAI) and optimal GC content. In silico cloning into the pET28+(a) vector demonstrated efficient expression. Immune simulations indicated the vaccine's ability to initiate immune responses in humans, mirroring real-life scenarios. Based on these comprehensive findings, we propose that our developed vaccine has the potential to confer robust immunity against H. pylori and F. nucleatum infections.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Tanjin Tamanna
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore, Bangladesh
- Bioinformatics and Microbial Biotechnology Laboratory, Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Md Shahedur Rahman
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore, Bangladesh
- Bioinformatics and Microbial Biotechnology Laboratory, Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore, Bangladesh
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2
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Graham DY. Helicobacter pylori. Curr Top Microbiol Immunol 2024; 445:127-154. [PMID: 34224014 DOI: 10.1007/82_2021_235] [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: 10/19/2022]
Abstract
Helicobacter pylori (H. pylori) is an important human pathogen etiologically associated with peptic ulcers and gastric cancer. The infection is present in approximately one-half of the world's population. Population-based H. pylori eradiation has confirmed that cure or prevention of the infection produces a marked reduction in gastric cancer and peptic ulcer disease. Antimicrobial therapy has become increasingly ineffective, and complexity and costs of antimicrobial therapy for infected individuals residing in and, immigrating from, the developing world combined with the cost of treatment for cancer make vaccine development a cost-effective alternative. Challenge studies allowed making a "go-no go" decision regarding vaccine effectiveness. We provide detailed protocols regarding challenge strain selection and administration as well as guidance regarding the clinical and laboratory tests used to confirm and monitor experimental infection. Experience shows that reliance of noninvasive methods led to the erroneous conclusion that some subjects were not infected. The current data suggests that histologic assessment of gastric mucosal biopsies may be one of the most sensitive and specific means of assessment of the presence of experimental infection as well as of successful H. pylori eradication. We recommend detailed recommendations for acquiring, processing, embedding, sectioning, and examining the gastric biopsies.
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Affiliation(s)
- David Y Graham
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, RM 3A-390A (111D), 2002 Holcombe Boulevard, Houston, TX, 77030, USA.
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3
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Zhang Z, Chen X, Li B, Xia T, Wu X, Wu C. Helicobacter pylori induces urease subunit B-specific CD8 + T cell responses in infected individuals via cytosolic pathway of cross-presentation. Helicobacter 2023; 28:e13005. [PMID: 37382428 DOI: 10.1111/hel.13005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 06/04/2023] [Accepted: 06/19/2023] [Indexed: 06/30/2023]
Abstract
BACKGROUND Urease subunit B (UreB), a conserved and key virulence factor of Helicobacter pylori (H. pylori), can induce the host CD4+ T cell immune responses to provide protection, but less is known regarding CD8+ T cell responses. The characteristics of H. pylori-specific CD8+ T cell responses and the mechanism underlying antigen processing and presentation pathways remain unclear. This study was focus on protective antigen recombinant UreB (rUreb) to detect specific CD8+ T cell responses in vitro and elucidate the mechanism of UreB antigen processing and presentation. METHODS The peripheral blood mononuclear cells (PBMCs) collected from H. pylori-infected individuals were stimulated with rUreB in vitro to detect specific CD8+ T cell responses after co-culture with rUreB-pulsed autologous hMDCs. Through blocking assay, we investigated the potential pathway of UreB antigen processing and presentation via the cytosolic pathway or vacuolar pathway. The cytokines production of UreB specific CD8+ T cell were evaluated as well. RESULTS We demonstrated UreB can induce specific CD8+ T cell immune responses in H. pylori infected individuals. Importantly, we characterized that UreB were mainly processed by proteasome instead of lysosomal proteases and presented through cytosolic pathway of cross-presentation, which requires endoplasmic reticulum-Golgi transport and newly synthesized MHC-I molecules, to induce functional-specific CD8+ T cell (IFN-γ + TNF-α + Grz A+ Grz B+) responses. CONCLUSIONS These results suggest that H. pylori UreB induces specific CD8+ T cell responses through cytosolic pathway of cross-presentation in infected individuals.
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Affiliation(s)
- Zelin Zhang
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Xingchi Chen
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Bin Li
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Tingting Xia
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Xiaobin Wu
- Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Chao Wu
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
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4
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He T, Zhang F, Zhang J, Wei S, Ning J, Yuan H, Li B. UreB immunodominant epitope-specific CD8 + T-cell responses were beneficial in reducing gastric symptoms in Helicobacter pylori-infected individuals. Helicobacter 2023; 28:e12959. [PMID: 36828665 DOI: 10.1111/hel.12959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/18/2023] [Accepted: 02/06/2023] [Indexed: 02/26/2023]
Abstract
BACKGROUND AND AIMS Although Helicobacter pylori is recognized as an extracellular infection bacterium, it can lead to an increase in the number of CD8+ T cells after infection. At present, the characteristics of H. pylori antigen-specific CD8+ T cells and the epitope response have not been elucidated. This study was focused on putative protective antigen UreB to detect specific CD8+ T-cell responses in vitro and screen for predominant response epitopes. METHODS The PBMCs collected from H. pylori-infected individuals were stimulated by UreB peptide pools in vitro to identify the immunodominant CD8+ T-cell epitopes. Furthermore, their HLA restriction characteristics were detected accordingly by NGS. Finally, the relationship between immunodominant responses and appearance of gastric symptoms after H. pylori infection was conducted. RESULTS UreB-specific CD8+ T-cell responses were detected in H. pylori-infected individuals. Three of UreB dominant epitopes (A-2 (UreB443-451 : GVKPNMIIK), B-4 (UreB420-428 : SEYVGSVEV), and C-1 (UreB5-13 : SRKEYVSMY)) were firstly identified and mainly presented by HLA-A*1101, HLA-B*4001 and HLA-C*0702 alleles, respectively. C-1 responses were mostly occurred in H. pylori-infected subjects without gastric symptoms and may alleviate the degree of gastric inflammation. CONCLUSIONS The UreB dominant epitope-specific CD8+ T-cell response was closely related to the gastric symptoms after H. pylori infection, and the C-1 (UreB5-13 ) dominant peptides may be protective epitopes.
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Affiliation(s)
- Taojun He
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Fang Zhang
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jin Zhang
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Shanshan Wei
- Department of Digestive Endoscopy Center, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jie Ning
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Hanmei Yuan
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Bin Li
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
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5
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Ghasemi A, Wang S, Sahay B, Abbott JR, Curtiss R. Protective immunity enhanced Salmonella vaccine vectors delivering Helicobacter pylori antigens reduce H. pylori stomach colonization in mice. Front Immunol 2022; 13:1034683. [PMID: 36466847 PMCID: PMC9716130 DOI: 10.3389/fimmu.2022.1034683] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/31/2022] [Indexed: 08/18/2024] Open
Abstract
Helicobacter pylori is a major cause of gastric mucosal inflammation, peptic ulcers, and gastric cancer. Emerging antimicrobial-resistant H. pylori has hampered the effective eradication of frequent chronic infections. Moreover, a safe vaccine is highly demanded due to the absence of effective vaccines against H. pylori. In this study, we employed a new innovative Protective Immunity Enhanced Salmonella Vaccine (PIESV) vector strain to deliver and express multiple H. pylori antigen genes. Immunization of mice with our vaccine delivering the HpaA, Hp-NAP, UreA and UreB antigens, provided sterile protection against H. pylori SS1 infection in 7 out of 10 tested mice. In comparison to the control groups that had received PBS or a PIESV carrying an empty vector, immunized mice exhibited specific and significant cellular recall responses and antigen-specific serum IgG1, IgG2c, total IgG and gastric IgA antibody titers. In conclusion, an improved S. Typhimurium-based live vaccine delivering four antigens shows promise as a safe and effective vaccine against H. pylori infection.
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Affiliation(s)
- Amir Ghasemi
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, Florida, FL, United States
| | - Shifeng Wang
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, Florida, FL, United States
| | - Bikash Sahay
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, Florida, FL, United States
| | - Jeffrey R. Abbott
- Department of Comparative, Diagnostic and Population Medicine, University of Florida, Gainesville, FL, United States
| | - Roy Curtiss
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, Florida, FL, United States
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Malfertheiner P, Megraud F, Rokkas T, Gisbert JP, Liou JM, Schulz C, Gasbarrini A, Hunt RH, Leja M, O'Morain C, Rugge M, Suerbaum S, Tilg H, Sugano K, El-Omar EM. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut 2022; 71:gutjnl-2022-327745. [PMID: 35944925 DOI: 10.1136/gutjnl-2022-327745] [Citation(s) in RCA: 575] [Impact Index Per Article: 191.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/21/2022] [Indexed: 01/06/2023]
Abstract
Helicobacter pyloriInfection is formally recognised as an infectious disease, an entity that is now included in the International Classification of Diseases 11th Revision. This in principle leads to the recommendation that all infected patients should receive treatment. In the context of the wide clinical spectrum associated with Helicobacter pylori gastritis, specific issues persist and require regular updates for optimised management.The identification of distinct clinical scenarios, proper testing and adoption of effective strategies for prevention of gastric cancer and other complications are addressed. H. pylori treatment is challenged by the continuously rising antibiotic resistance and demands for susceptibility testing with consideration of novel molecular technologies and careful selection of first line and rescue therapies. The role of H. pylori and antibiotic therapies and their impact on the gut microbiota are also considered.Progress made in the management of H. pylori infection is covered in the present sixth edition of the Maastricht/Florence 2021 Consensus Report, key aspects related to the clinical role of H. pylori infection were re-evaluated and updated. Forty-one experts from 29 countries representing a global community, examined the new data related to H. pylori infection in five working groups: (1) indications/associations, (2) diagnosis, (3) treatment, (4) prevention/gastric cancer and (5) H. pylori and the gut microbiota. The results of the individual working groups were presented for a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in various clinical fields.
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Affiliation(s)
- Peter Malfertheiner
- Medical Department 2, LMU, Munchen, Germany
- Department of Radiology, LMU, Munchen, Germany
| | - Francis Megraud
- INSERM U853 UMR BaRITOn, University of Bordeaux, Bordeaux, France
| | - Theodore Rokkas
- Gastroenterology, Henry Dunant Hospital Center, Athens, Greece
- Medical School, European University, Nicosia, Cyprus
| | - Javier P Gisbert
- Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Jyh-Ming Liou
- Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Christian Schulz
- Medical Department 2, LMU, Munchen, Germany
- Partner Site Munich, DZIF, Braunschweig, Germany
| | - Antonio Gasbarrini
- Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy
| | - Richard H Hunt
- Medicine, McMaster University, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada
| | - Marcis Leja
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
| | - Colm O'Morain
- Faculty of Health Sciences, Trinity College Dublin, Dublin, Ireland
| | - Massimo Rugge
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Padova, Italy
- Veneto Tumor Registry (RTV), Padova, Italy
| | - Sebastian Suerbaum
- Partner Site Munich, DZIF, Braunschweig, Germany
- Max von Pettenkofer Institute, LMU, Munchen, Germany
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medizinische Universitat Innsbruck, Innsbruck, Austria
| | - Kentaro Sugano
- Department of Medicine, Jichi Medical School, Tochigi, Japan
| | - Emad M El-Omar
- Department of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK
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7
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Deng R, Zheng H, Cai H, Li M, Shi Y, Ding S. Effects of helicobacter pylori on tumor microenvironment and immunotherapy responses. Front Immunol 2022; 13:923477. [PMID: 35967444 PMCID: PMC9371381 DOI: 10.3389/fimmu.2022.923477] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 07/04/2022] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori is closely associated with gastric cancer. During persistent infection, Helicobacter pylori can form a microenvironment in gastric mucosa which facilitates the survival and colony formation of Helicobacter pylori. Tumor stromal cells are involved in this process, including tumor-associated macrophages, mesenchymal stem cells, cancer-associated fibroblasts, and myeloid-derived suppressor cells, and so on. The immune checkpoints are also regulated by Helicobacter pylori infection. Helicobacter pylori virulence factors can also act as immunogens or adjuvants to elicit or enhance immune responses, indicating their potential applications in vaccine development and tumor immunotherapy. This review highlights the effects of Helicobacter pylori on the immune microenvironment and its potential roles in tumor immunotherapy responses.
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Affiliation(s)
- Ruiyi Deng
- Peking University Third Hospital, Research Center of Clinical Epidemiology, Beijing, China
- Peking University Health Science Center, Peking University First Medical School, Beijing, China
| | - Huiling Zheng
- Peking University Third Hospital, Department of Gastroenterology, Beijing, China
| | - Hongzhen Cai
- Peking University Third Hospital, Research Center of Clinical Epidemiology, Beijing, China
- Peking University Health Science Center, Peking University First Medical School, Beijing, China
| | - Man Li
- Peking University Third Hospital, Research Center of Clinical Epidemiology, Beijing, China
- Peking University Health Science Center, Peking University Third Medical School, Beijing, China
| | - Yanyan Shi
- Peking University Third Hospital, Research Center of Clinical Epidemiology, Beijing, China
| | - Shigang Ding
- Peking University Third Hospital, Department of Gastroenterology, Beijing, China
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8
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Ansari H, Tahmasebi-Birgani M, Bijanzadeh M. DNA vaccine containing Flagellin A gene induces significant immune responses against Helicobacter pylori infection: An in vivo study. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:796-804. [PMID: 34630957 PMCID: PMC8487603 DOI: 10.22038/ijbms.2021.54415.12227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 05/23/2021] [Indexed: 11/17/2022]
Abstract
Objective(s): Helicobacter pylori is one of the most prevalent human infectious agents that is directly involved in various upper digestive tract diseases. Although antibiotics-based therapy and proton pump inhibitors eradicate the bacteria mostly, their effectiveness has been declined recently due to emergence of antibiotic-resistant strains. Development of a DNA vaccine is a promising approach against bacterial pathogens. Genes encoding motility factors are promising immunogens to develop a DNA vaccine against H. pylori infection due to critical role of these genes in bacterial attachment and colonization within the gastric lumen. The present study aimed to synthesize a DNA vaccine construct based on the Flagellin A gene (flaA), the predominant flagellin subunit in H. pylori flagella. Materials and Methods: The coding sequence of flaA was amplified through PCR and sub-cloned in the pBudCE4.1 vector. The recombinant vector was introduced into the human dermal fibroblast cells, and its potency to express the flaA protein was analyzed using SDS-PAGE. The recombinant construct was intramuscularly (IM) injected into the mice, and the profiles of cytokines and immunoglobulins were measured using ELISA. Results: It has been found that flaA was successfully expressed in cells. Recombinant-vector also increased the serum levels of evaluated cytokines and immunoglobulins in mice. Conclusion: These findings showed that the pBudCE4.1-flaA construct was able to activate the immune responses. This study is the first step towards synthesis of recombinant-construct based on the flaA gene. Immunization with such construct may inhibit the H. pylori-associated infection; however, further experiments are urgent.
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Affiliation(s)
- Hossein Ansari
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Biotechnology, Islamic Azad University of Ahvaz, Ahvaz Branch, Ahvaz, Iran
| | - Maryam Tahmasebi-Birgani
- Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahdi Bijanzadeh
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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9
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Ghosh P, Bhakta S, Bhattacharya M, Sharma AR, Sharma G, Lee SS, Chakraborty C. A Novel Multi-Epitopic Peptide Vaccine Candidate Against Helicobacter pylori: In-Silico Identification, Design, Cloning and Validation Through Molecular Dynamics. Int J Pept Res Ther 2021; 27:1149-1166. [PMID: 33495694 PMCID: PMC7816556 DOI: 10.1007/s10989-020-10157-w] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/30/2020] [Indexed: 01/22/2023]
Abstract
Helicobacter pylori is a highly potential pathogen to colonize in the human stomach. This bacterial strain is now alarming serious health concern all over the world. Combating through available drugs is a difficult task due to lack of appropriate common targets against genetically diverse strains. Therefore, the developments of effective targets vaccines require alternative strategies to eliminate the H. pylori infection. In this study, we developed a novel vaccine construct using B-cell derived T-cell epitopes from four target antigenic proteins (HpaA, FlaA, FlaB and Omp18), and found the induction of possible immune response using advanced immunoinformatics approaches. In order to boost immune system, we tagged adjuvant (50S ribosomal protein L7/L12) with a suitable linker at the N-terminus side of vaccine sequence. Protein–protein docking between human Toll like receptor 5 (TLR5) and vaccine construct help to predict the way of inductive signaling that leads to immune-response. The calculated negative score (− 151.4, + / − 8.7) of molecular docking complex signify the best binding interface. Molecular dynamics simulation studies confirmed the proper docking between TLR5 and vaccine candidate. Moreover, Normal mode analysis (NMA) calculates the molecular motion of the docking complex. The low eigenvalue (2.935e−05) indicates the stable and flexible molecular motion in the binding interaction side. Finally, in-silico cloning of vaccine candidate was performed using expression vector pET28b (+) with the optimized restriction sites.
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Affiliation(s)
- Pratik Ghosh
- Department of Zoology, Vidyasagar University, Midnapore, West Bengal 721102 India
| | - Swarnav Bhakta
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Barasat-Barrackpore Rd, Kolkata, West Bengal 700126 India
| | - Manojit Bhattacharya
- Department of Zoology, Fakir Mohan University, Vyasa Vihar, Balasore, Odisha 756020 India
| | - Ashish Ranjan Sharma
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon-si, 24252 Gangwon-do Republic of Korea
| | - Garima Sharma
- Department of Biomedical Science & Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon-si, 24341 Gangwon Do Republic of Korea
| | - Sang-Soo Lee
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon-si, 24252 Gangwon-do Republic of Korea
| | - Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Barasat-Barrackpore Rd, Kolkata, West Bengal 700126 India.,Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon-si, 24252 Gangwon-do Republic of Korea
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10
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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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11
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Wang J, Zhang Y, Zhu Y, Liu J, Chen Y, Cao X, Yang Y. Total Synthesis and Immunological Evaluation of the Tri-d-glycero-d-manno-heptose Antigen of the Lipopolysaccharide as a Vaccine Candidate against Helicobacter pylori. Org Lett 2020; 22:8780-8785. [DOI: 10.1021/acs.orglett.0c03105] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Junchang Wang
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Yiyue Zhang
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Yirong Zhu
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Junru Liu
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Yan Chen
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Xin Cao
- Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai Medical College, 179 Fenglin Road, Shanghai 200032, China
| | - You Yang
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
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12
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Meyer TF, Morey P. A Future for a Vaccine Against the Cancer-Inducing Bacterium Helicobacter pylori? MUCOSAL VACCINES 2020:579-596. [DOI: 10.1016/b978-0-12-811924-2.00033-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Tian G, Qin C, Liu Z, Shen D, Zou X, Fu J, Hu J, Seeberger PH, Yin J. Total synthesis of theHelicobacter pyloriserotype O2 O-antigen α-(1 → 2)- and α-(1 → 3)-linked oligoglucosides. Chem Commun (Camb) 2020; 56:344-347. [DOI: 10.1039/c9cc07915g] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Unique α-(1 → 2)- and α-(1 → 3)-linked oligoglucosides from theH. pyloriserotype O2 O-antigen were synthesized with exclusive α-selectivity using remote participation effects.
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Affiliation(s)
- Guangzong Tian
- Key Laboratory of Carbohydrate Chemistry and Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi 214122
| | - Chunjun Qin
- Key Laboratory of Carbohydrate Chemistry and Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi 214122
| | - Zhonghua Liu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi 214122
| | - Dacheng Shen
- Department of Biomolecular Systems
- Max-Plank Institute of Colloids and Interfaces
- 14476 Potsdam
- Germany
| | - Xiaopeng Zou
- Key Laboratory of Carbohydrate Chemistry and Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi 214122
| | - Junjie Fu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi 214122
| | - Jing Hu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi 214122
| | - Peter H. Seeberger
- Department of Biomolecular Systems
- Max-Plank Institute of Colloids and Interfaces
- 14476 Potsdam
- Germany
| | - Jian Yin
- Key Laboratory of Carbohydrate Chemistry and Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi 214122
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Salillas S, Alías M, Michel V, Mahía A, Lucía A, Rodrigues L, Bueno J, Galano-Frutos JJ, De Reuse H, Velázquez-Campoy A, Carrodeguas JA, Sostres C, Castillo J, Aínsa JA, Díaz-de-Villegas MD, Lanas Á, Touati E, Sancho J. Design, Synthesis, and Efficacy Testing of Nitroethylene- and 7-Nitrobenzoxadiazol-Based Flavodoxin Inhibitors against Helicobacter pylori Drug-Resistant Clinical Strains and in Helicobacter pylori-Infected Mice. J Med Chem 2019; 62:6102-6115. [DOI: 10.1021/acs.jmedchem.9b00355] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Sandra Salillas
- Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain
- Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain
| | - Miriam Alías
- Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain
| | - Valérie Michel
- Helicobacter Pathogenesis Unit, Department of Microbiology, CNRS ERL6002, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris 75724, France
| | - Alejandro Mahía
- Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain
- Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain
| | - Ainhoa Lucía
- Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain
| | - Liliana Rodrigues
- Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain
| | | | - Juan José Galano-Frutos
- Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain
- Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain
| | - Hilde De Reuse
- Helicobacter Pathogenesis Unit, Department of Microbiology, CNRS ERL6002, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris 75724, France
| | - Adrián Velázquez-Campoy
- Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain
- Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain
- Fundación ARAID, Gobierno de Aragón, Zaragoza 50009, Spain
| | - José Alberto Carrodeguas
- Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain
- Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain
| | - Carlos Sostres
- Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain
| | | | - José Antonio Aínsa
- Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain
- Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain
| | | | - Ángel Lanas
- Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain
| | - Eliette Touati
- Helicobacter Pathogenesis Unit, Department of Microbiology, CNRS ERL6002, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris 75724, France
| | - Javier Sancho
- Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, Zaragoza 50018, Spain
- Aragon Health Research Institute (IIS Aragón), Zaragoza 50009, Spain
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15
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Pasala C, Katari SK, Nalamolu RM, Bitla AR, Amineni U. Hierarchical-Clustering, Scaffold-Mining Exercises and Dynamics Simulations for Effectual Inhibitors Against Lipid-A Biosynthesis of Helicobacter pylori. Cell Mol Bioeng 2019; 12:255-274. [PMID: 31719913 DOI: 10.1007/s12195-019-00572-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 04/23/2019] [Indexed: 12/19/2022] Open
Abstract
Introduction Treatment failures of standard regimens and new strains egression are due to the augmented drug resistance conundrum. These confounding factors now became the drug designers spotlight to implement therapeutics against Helicobacter pylori strains and to safeguard infected victims with devoid of adverse drug reactions. Thereby, to navigate the chemical space for medicine, paramount vital drug target opting considerations should be imperative. The study is therefore aimed to develop potent therapeutic variants against an insightful extrapolative, common target LpxC as a follow-up to previous studies. Methods We explored the relationships between existing inhibitors and novel leads at the scaffold level in an appropriate conformational plasticity for lead-optimization campaign. Hierarchical-clustering and shape-based screening against an in-house library of > 21 million compounds resulted in panel of 11,000 compounds. Rigid-receptor docking through virtual screening cascade, quantum-polarized-ligand, induced-fit dockings, post-docking processes and system stability assessments were performed. Results After docking experiments, an enrichment performance unveiled seven ranked actives better binding efficiencies with Zinc-binding potency than substrate and in-actives (decoy-set) with ROC (1.0) and area under accumulation curve (0.90) metrics. Physics-based membrane permeability accompanied ADME/T predictions and long-range dynamic simulations of 250 ns chemical time have depicted good passive diffusion with no toxicity of leads and sustained consistency of lead1-LpxC in the physiological milieu respectively. Conclusions In the study, as these static outcomes obtained from this approach competed with the substrate and existing ligands in binding affinity estimations as well as positively correlated from different aspects of predictions, which could facilitate promiscuous new chemical entities against H. pylori.
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Affiliation(s)
- Chiranjeevi Pasala
- Bioinformatics Centre, Department of Bioinformatics, SVIMS University, Tirupati, 517507 AP India
| | - Sudheer Kumar Katari
- Bioinformatics Centre, Department of Bioinformatics, SVIMS University, Tirupati, 517507 AP India
| | | | - Aparna R Bitla
- Department of Biochemistry, SVIMS University, Tirupati, 517507 AP India
| | - Umamaheswari Amineni
- Bioinformatics Centre, Department of Bioinformatics, SVIMS University, Tirupati, 517507 AP India
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Current and Future Treatment of Helicobacter pylori Infections. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:211-225. [PMID: 31016626 DOI: 10.1007/5584_2019_367] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Helicobacter pylori is one of the most common human pathogens and it has been estimated that about 50% of the world's population is currently infected. The present consensus is that, unless there are compelling reasons, all H. pylori infections should be cured. Since the 1990s, different national and international guidelines for the management of H. pylori-related diseases have been published and periodically updated regarding indications for treatment, diagnostic procedures, and preferred treatment regimens. Most guidelines provide sophisticated meta-analyses examining the outcome of different regimens done in regions with variable, often high rates of resistance to antibiotics, for which the prevalence and effects of resistance was often ignored. Although successful antimicrobial therapy must be susceptibility-based, increasing antimicrobial resistance and general unavailability of susceptibility testing have required clinicians to generally rely on empiric regimens. Antibiotics resistance of H. pylori has reached alarming high levels worldwide, which has an effect to efficacy of treatment. The recommendations should provide regimes for multi-resistant infections or for those where susceptibility testing is unavailable or refused. The first rule is to use only proven locally effective therapies. Because of patient intolerances, drug allergies, and local experiences, the clinicians should have at least two options for first-line therapy. As with any antimicrobial therapy, a thorough review of prior antibiotic use is invaluable to identify the presence of probably resistance. The second key is patient education regarding potential and expected side-effects and the importance of completing the course of antibiotics. We also review here triple therapies, sequential-concomitant, hybrid therapies, bismuth therapies, dual therapy, vonoprazan, modern antibiotic treatments, probiotics and vaccination.
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Pasala C, Chilamakuri CSR, Katari SK, Nalamolu RM, Bitla AR, Amineni U. Epitope-driven common subunit vaccine design against H. pylori strains. J Biomol Struct Dyn 2018; 37:3740-3750. [DOI: 10.1080/07391102.2018.1526714] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Chiranjeevi Pasala
- Bioinformatics Centre, Department of Bioinformatics, SVIMS University, Tirupati, AP, India
| | | | - Sudheer Kumar Katari
- Bioinformatics Centre, Department of Bioinformatics, SVIMS University, Tirupati, AP, India
| | | | - Aparna R. Bitla
- Department of Biochemistry, SVIMS University, Tirupati, AP, India
| | - Umamaheswari Amineni
- Bioinformatics Centre, Department of Bioinformatics, SVIMS University, Tirupati, AP, India
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Malfertheiner P, Selgrad M, Wex T, Romi B, Borgogni E, Spensieri F, Zedda L, Ruggiero P, Pancotto L, Censini S, Palla E, Kanesa-Thasan N, Scharschmidt B, Rappuoli R, Graham DY, Schiavetti F, Del Giudice G. Efficacy, immunogenicity, and safety of a parenteral vaccine against Helicobacter pylori in healthy volunteers challenged with a Cag-positive strain: a randomised, placebo-controlled phase 1/2 study. Lancet Gastroenterol Hepatol 2018; 3:698-707. [DOI: 10.1016/s2468-1253(18)30125-0] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 03/29/2018] [Accepted: 04/05/2018] [Indexed: 12/14/2022]
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Stubljar D, Jukic T, Ihan A. How far are we from vaccination against Helicobacter pylori infection? Expert Rev Vaccines 2018; 17:935-945. [PMID: 30238819 DOI: 10.1080/14760584.2018.1526680] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Helicobacter pylori infection results in chronic gastritis, peptic ulcer, or gastric cancer; therefore, eradication of this bacterium is essential. The strategy for developing effective vaccines against H. pylori entails immunization of mice with a combination of classical and recombinant H. pylori antigens, but this has proven to be onerous in all cases. AREAS COVERED We have reviewed literature databases in PubMed and Scopus using the key words H. pylori, vaccine, and vaccination and have conducted a systematic review of published clinical trials and animal model studies on vaccines against H. pylori and have tried to summarize why the vaccines are not effective or only partially effective. EXPERT COMMENTARY This is the perfect time to review vaccine development against H. pylori as, after several failed attempts, promising results were reported by Zeng et al. in 2015. Successful vaccine development requires knowledge of both the immune mechanisms active during natural infection by H. pylori, owing to the complicated host response against the pathogen, and the factors that allow the persistence of bacteria, such as genetic diversity of H. pylori. Moreover, various clinical trials are needed to prove vaccine efficacy.
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Affiliation(s)
- David Stubljar
- a Department of Research & Development , In-Medico , Metlika , Slovenia
| | - Tomislav Jukic
- b Department of Biomedicine and Public Health , Faculty of Medicine Osijek , Osijek , Croatia
| | - Alojz Ihan
- c Medical Faculty of Ljubljana , Institute of Microbiology and Immunology , Ljubljana , Slovenia
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Zou X, Qin C, Pereira CL, Tian G, Hu J, Seeberger PH, Yin J. Synergistic Glycosylation as Key to the Chemical Synthesis of an Outer Core Octasaccharide ofHelicobacter pylori. Chemistry 2018; 24:2868-2872. [DOI: 10.1002/chem.201800049] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Indexed: 12/17/2022]
Affiliation(s)
- Xiaopeng Zou
- Key Laboratory of Carbohydrate Chemistry and Biotechnology; Ministry of Education; School of Biotechnology; Jiangnan University; Lihu Avenue 1800 Wuxi Jiangsu province 214122 P. R. China
- Department of Biomolecular Systems; Max Planck Institute of Colloids and Interfaces; Am Mühlenberg 1 14476 Potsdam Germany
| | - Chunjun Qin
- Key Laboratory of Carbohydrate Chemistry and Biotechnology; Ministry of Education; School of Biotechnology; Jiangnan University; Lihu Avenue 1800 Wuxi Jiangsu province 214122 P. R. China
- Department of Biomolecular Systems; Max Planck Institute of Colloids and Interfaces; Am Mühlenberg 1 14476 Potsdam Germany
| | - Claney L. Pereira
- Department of Biomolecular Systems; Max Planck Institute of Colloids and Interfaces; Am Mühlenberg 1 14476 Potsdam Germany
| | - Guangzong Tian
- Key Laboratory of Carbohydrate Chemistry and Biotechnology; Ministry of Education; School of Biotechnology; Jiangnan University; Lihu Avenue 1800 Wuxi Jiangsu province 214122 P. R. China
- Department of Biomolecular Systems; Max Planck Institute of Colloids and Interfaces; Am Mühlenberg 1 14476 Potsdam Germany
| | - Jing Hu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology; Ministry of Education; School of Biotechnology; Jiangnan University; Lihu Avenue 1800 Wuxi Jiangsu province 214122 P. R. China
| | - Peter H. Seeberger
- Department of Biomolecular Systems; Max Planck Institute of Colloids and Interfaces; Am Mühlenberg 1 14476 Potsdam Germany
| | - Jian Yin
- Key Laboratory of Carbohydrate Chemistry and Biotechnology; Ministry of Education; School of Biotechnology; Jiangnan University; Lihu Avenue 1800 Wuxi Jiangsu province 214122 P. R. China
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Mirzaei N, Poursina F, Moghim S, Rashidi N, Ghasemian Safaei H. The study of H. pylori putative candidate factors for single- and multi-component vaccine development. Crit Rev Microbiol 2017; 43:631-650. [PMID: 28581361 DOI: 10.1080/1040841x.2017.1291578] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Helicobacter pylori has grown to colonize inside the stomach of nearly half of the world's population, turning into the most prevalent infections in the universe. Medical care failures noticeably confirm the need for a vaccine to hinder or deal with H. pylori. This review is planned to discuss the most known factors as a vaccine candidate, including single (AhpC, BG, CagA, KatA, Fla, Hsp, HWC, Lpp, LPS, NAP, OMP, OMV, SOD, Tpx, Urease, VacA) and multi-component vaccines. Many promising results in the field of single and multivalent vaccine can be seen, but there is no satisfactory outcome and neither a prophylactic nor a therapeutic vaccine to treat or eradicate the infection in human has been acquired. Hence, selecting suitable antigen is an important factor as an appropriate adjuvant. Taken all together, the development of efficient anti-H. pylori vaccines relies on the fully understanding of the interactions between H. pylori and its host immune system. Therefore, more work should be done on epitope mapping, analysis of molecular structure, and determination of the antigen determinant region as well due to design a vaccine, preferably a multi-component vaccine to elicit specific CD4 T-cell responses that are required for H. pylori vaccine efficacy.
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Affiliation(s)
- Nasrin Mirzaei
- a Department of Microbiology , Tonekabon Branch, Islamic Azad University , Tonekabon , Iran
| | - Farkhondeh Poursina
- b Department of Microbiology , Isfahan University of Medical Sciences , Isfahan , Iran
| | - Sharareh Moghim
- b Department of Microbiology , Isfahan University of Medical Sciences , Isfahan , Iran
| | - Niloufar Rashidi
- c Department of Laboratory Sciences , Ahvaz University of Medical Sciences , Ahvaz , Iran
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Meza B, Ascencio F, Sierra-Beltrán AP, Torres J, Angulo C. A novel design of a multi-antigenic, multistage and multi-epitope vaccine against Helicobacter pylori: An in silico approach. INFECTION GENETICS AND EVOLUTION 2017; 49:309-317. [DOI: 10.1016/j.meegid.2017.02.007] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 02/02/2017] [Accepted: 02/05/2017] [Indexed: 02/07/2023]
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The Immunomodulator VacA Promotes Immune Tolerance and Persistent Helicobacter pylori Infection through Its Activities on T-Cells and Antigen-Presenting Cells. Toxins (Basel) 2016; 8:toxins8060187. [PMID: 27322319 PMCID: PMC4926153 DOI: 10.3390/toxins8060187] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 06/07/2016] [Accepted: 06/08/2016] [Indexed: 12/22/2022] Open
Abstract
VacA is a pore-forming toxin that has long been known to induce vacuolization in gastric epithelial cells and to be linked to gastric disorders caused by H. pylori infection. Its role as a major colonization and persistence determinant of H. pylori is less well-understood. The purpose of this review is to discuss the various target cell types of VacA and its mechanism of action; specifically, we focus on the evidence showing that VacA targets myeloid cells and T-cells to directly and indirectly prevent H. pylori-specific T-cell responses and immune control of the infection. In particular, the ability of VacA-proficient H. pylori to skew T-cell responses towards regulatory T-cells and the effects of Tregs on H. pylori chronicity are highlighted. The by-stander effects of VacA-driven immunomodulation on extragastric diseases are discussed as well.
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Shan W, Kung HF, Ge R. Comparison of Iron-Binding Ability Between Thr70-NapA and Ser70-NapA of Helicobacter pylori. Helicobacter 2016; 21:192-200. [PMID: 26347349 DOI: 10.1111/hel.12266] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND The neutrophil-activating protein (NapA) of Helicobacter pylori (H. pylori), with DNA-binding and iron seizing properties, is a fundamental virulence factor involved in H. pylori-related diseases. Compared with Ser70-NapA strain, Thr70-NapA strain is more intimately correlated with iron-deficiency anemia. METHODS To investigate whether two types of proteins differ in iron-binding ability, mutated Thr70-NapA and Ser70-NapA strains were established. Isothermal titration calorimetry (ITC) method was conducted to measure the binding between the NapA protein and Fe(2+) . The structural changes of NapA protein were also tested during iron interaction by fast protein liquid chromatography (FPLC) and circular dichroism (CD) methods. DNA-binding assay was performed for evaluate the affinity of both mutated and wild types of NapA with DNA. RESULTS Mutated Thr70-NapA had higher iron-binding ability than wild Ser70-NapA. The structural stability of Thr70-NapA was disrupted and became more active along with the rising concentration of Fe(2+) , whereas no similar association was observed between Ser70-NapA and Fe(2+) level. When the iron/protein molar ratio ranged from 10 to 20, both Ser70-NapA and Thr70-NapA displayed weaker DNA-binding ability. CONCLUSIONS Thr70-NapA has much stronger ability to sequester ferrous ion compared with Ser70-NapA in H. pylori. In addition, the DNA-binding property of NapA is dependent upon the Fe(2+) concentration.
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Affiliation(s)
- Weiran Shan
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, College of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Hsiang-Fu Kung
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ruiguang Ge
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, College of Life Sciences, Sun Yat-Sen University, Guangzhou, China
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Why Don't We Have a Vaccine Against……….? Part 3. Bacteria, Too. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2016. [DOI: 10.1097/ipc.0000000000000363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Abstract
Helicobacter pylori is a ubiquitous gastropathogen infecting more than half of the world population. It is associated with dyspepsia, gastritis, gastroduodenal ulcers, mucus-associated lymphoid tissue lymphoma and gastric carcinoma. Current recommended therapy does not eradicate infection in all treated cases and at least 20% post-treatment patients continue to suffer. Salvage therapy helps some of these nonresponders, but resistance to available antibiotics is mounting. Hence, its treatment still remains a daunting task for the practicing physician. Novel medications with improved efficacy and tolerability and with less chances of resistance are required. The present review attempts to discuss the newer patents in this field, which demonstrate a promising future role in the management of H. pylori infection and its consequent problems.
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Zeng M, Mao XH, Li JX, Tong WD, Wang B, Zhang YJ, Guo G, Zhao ZJ, Li L, Wu DL, Lu DS, Tan ZM, Liang HY, Wu C, Li DH, Luo P, Zeng H, Zhang WJ, Zhang JY, Guo BT, Zhu FC, Zou QM. Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2015; 386:1457-64. [PMID: 26142048 DOI: 10.1016/s0140-6736(15)60310-5] [Citation(s) in RCA: 195] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Helicobacter pylori is one of the most common gastric pathogens, affecting at least half the world's population, and is strongly associated with gastritis, peptic ulcer, gastric adenocarcinoma, and lymphoma. We aimed to assess the efficacy, safety, and immunogenicity of a three-dose oral recombinant H pylori vaccine in children in China. METHODS We did this randomised, double-blind, placebo-controlled, phase 3 trial at one centre in Ganyu County, Jiangsu Province, China. Healthy children aged 6-15 years without past or present H pylori infection were randomly assigned (1:1), via computer-generated randomisation codes in blocks of ten, to receive the H pylori vaccine or placebo. Participants, their guardians, and study investigators were masked to treatment allocation. The primary efficacy endpoint was the occurrence of H pylori infection within 1 year after vaccination. We did analysis in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT02302170. FINDINGS Between Dec 2, 2004, and March 19, 2005, we randomly assigned 4464 participants to either the vaccine group (n=2232) or the placebo group (n=2232), of whom 4403 (99%) participants completed the three-dose vaccination schedule and were included in the per-protocol efficacy analysis. We extended follow-up to 3 years. We recorded 64 events of H pylori infection within the first year (14 events in 2074·3 person-years at risk in the vaccine group vs 50 events in 2089·6 person-years at risk in the placebo group), resulting in a vaccine efficacy of 71·8% (95% CI 48·2-85·6). 157 (7%) participants in the vaccine group and 161 (7%) participants in the placebo group reported at least one adverse reaction. Serious adverse events were reported in five (<1%) participants in the vaccine group and seven (<1%) participants in the placebo group, but none was considered to be vaccination related. INTERPRETATION The oral recombinant H pylori vaccine was effective, safe, and immunogenic in H pylori-naive children. This vaccine could substantially reduce the incidence of H pylori infection; however, follow up over a longer period is needed to confirm the protection of the vaccine against H pylori-associated diseases. FUNDING Chongqing Kangwei Biological Technology.
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Affiliation(s)
- Ming Zeng
- National Institute for Food and Drug Control, Beijing, China
| | - Xu-Hu Mao
- College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Jing-Xin Li
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu Province, China
| | - Wen-De Tong
- Kangwei Biological Technology, Chongqing, China
| | - Bin Wang
- National Institute for Food and Drug Control, Beijing, China
| | - Yi-Ju Zhang
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu Province, China
| | - Gang Guo
- College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Zhi-Jing Zhao
- National Institute for Food and Drug Control, Beijing, China
| | - Liang Li
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu Province, China
| | - De-Lin Wu
- Ganyu County Center for Disease Control and Prevention, Lianyungang, Jiangsu Province, China
| | - Dong-Shui Lu
- College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Zhong-Ming Tan
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu Province, China
| | - Hao-Yu Liang
- National Institute for Food and Drug Control, Beijing, China
| | - Chao Wu
- College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Da-Han Li
- Ganyu County Center for Disease Control and Prevention, Lianyungang, Jiangsu Province, China
| | - Ping Luo
- College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Hao Zeng
- College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Wei-Jun Zhang
- College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Jin-Yu Zhang
- College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Bo-Tao Guo
- College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Feng-Cai Zhu
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu Province, China.
| | - Quan-Ming Zou
- College of Pharmacy, Third Military Medical University, Chongqing, China.
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Immunodominant epitope-specific Th1 but not Th17 responses mediate protection against Helicobacter pylori infection following UreB vaccination of BALB/c mice. Sci Rep 2015; 5:14793. [PMID: 26434384 PMCID: PMC4593181 DOI: 10.1038/srep14793] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 09/09/2015] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori (H. pylori) infects more than half of the world’s population, causing chronic gastritis, peptic ulcers and gastric cancer. Urease B subunit (UreB), a conserved protein of H. pylori, is capable of inducing specific CD4+ T-cell responses and provides protection against this infection. Previous studies have confirmed the effectiveness of rUreB subunit vaccines in generating CD4+ T-cell-mediated protection, but less is known regarding the roles of different subtypes of T-cell immunity, such as Th1, Th2 and Th17, particularly the immunodominant epitopes inducing specific CD4+ T-cell responses, in vaccine-mediated protection. In this study, we demonstrated that the vaccination of BALB/c mice with rUreB resulted in significant antigen-specific Th1 and Th17 immune responses. Importantly, two novel Th epitopes, UreB317–329 and UreB409–421, which are recognized by a major population of CD4+ T cells, were identified in immunized mice. Our results demonstrated that two novel epitopes can simultaneously induce Th1 and Th17 immune responses; however, only the epitope vaccine-induced CD4+ T-cells secreting IFN-γ mediated the protection against H. pylori; cells secreting IL-17A did not. Taken together, our results suggest that two novel immunodominant epitopes can induce Th1 and Th17 immune responses, but only the induced Th1 lymphocytes mediate protection against H. pylori.
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Lollini PL, Cavallo F, Nanni P, Quaglino E. The Promise of Preventive Cancer Vaccines. Vaccines (Basel) 2015; 3:467-89. [PMID: 26343198 PMCID: PMC4494347 DOI: 10.3390/vaccines3020467] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 06/04/2015] [Accepted: 06/08/2015] [Indexed: 01/01/2023] Open
Abstract
Years of unsuccessful attempts at fighting established tumors with vaccines have taught us all that they are only able to truly impact patient survival when used in a preventive setting, as would normally be the case for traditional vaccines against infectious diseases. While true primary cancer prevention is still but a long-term goal, secondary and tertiary prevention are already in the clinic and providing encouraging results. A combination of immunopreventive cancer strategies and recently approved checkpoint inhibitors is a further promise of forthcoming successful cancer disease control, but prevention will require a considerable reduction of currently reported toxicities. These considerations summed with the increased understanding of tumor antigens allow space for an optimistic view of the future.
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Affiliation(s)
- Pier-Luigi Lollini
- Department of Experimental Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, Bologna 40126, Italy.
| | - Federica Cavallo
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, Torino 10126, Italy.
| | - Patrizia Nanni
- Department of Experimental Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, Bologna 40126, Italy.
| | - Elena Quaglino
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, Torino 10126, Italy.
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Milani M, Sharifi Y, Rahmati-Yamchi M, Somi MH, Akbarzadeh A. Immunology and vaccines and nanovaccines for Helicobacter pylori infection. Expert Rev Vaccines 2015; 14:833-40. [PMID: 25645086 DOI: 10.1586/14760584.2015.1008460] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Helicobacter pylori infection is very common worldwide and is an important cause of gastritis, peptic ulcer disease, gastric mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma. Since the eradication requires treatment with multidrug regimens, prevention of primary infection by a suitable vaccine is attractive. Developing vaccines on the spot when and where an infection is breaking out might be possible, thanks to engineered nanoparticles. In this review, the nature of the host immune response to H. pylori infection is considered. We explain recent candidate vaccines and prophylactic or therapeutic immunization strategies for use against H. pylori. We also describe identification of different types of immune responses that may be related to protection against H. pylori infection. Thus, it seems that there is still a strong need to clarify the main protective immune response against H. pylori.
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Affiliation(s)
- Morteza Milani
- Liver and Gastrointestinal disease research center, Tabriz University of Medical Sciences, Tabriz, Iran
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Ruggiero P. Use of probiotics in the fight against Helicobacter pylori. World J Gastrointest Pathophysiol 2014; 5:384-91. [PMID: 25400981 PMCID: PMC4231502 DOI: 10.4291/wjgp.v5.i4.384] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 03/19/2014] [Accepted: 07/15/2014] [Indexed: 02/07/2023] Open
Abstract
After the discovery of Helicobacter pylori (H. pylori), and the evidence of its relationship with gastric diseases, antibiotic-based therapies were developed, which efficacy was however limited by antibiotic resistance and lack of patient compliance. A vaccine would overcome these drawbacks, but currently there is not any H. pylori vaccine licensed. In the frame of the studies aimed at finding alternative therapies or at increasing the efficacy of the current ones and/or reducing their side effects, the investigation on the use of probiotics plays an interesting role. In vitro and preclinical studies have shown the feasibility of this approach. Several clinical trials indicated that administration of probiotics can reduce the side effects of H. pylori eradication treatment, increasing tolerability, and often increases the overall efficacy. The results of these trials vary, likely reflecting the variety of probiotics assessed and that of the eradication treatment, as well as the differences in the geographic area that imply different H. pylori strains distribution, host susceptibility, and therapy efficacy. In conclusion, the use of probiotics appears promising as an adjuvant for the current H. pylori eradication treatment, though it still requires optimization.
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Abstract
The discovery of Helicobacter pylori three decades ago is a modern medical success story. It markedly changed our understanding of the pathophysiology of gastroduodenal diseases and led to an improvement in the treatment of diseases related to H. pylori infection. Many of these diseases (such as ulcer disease and mucosal associated lymphoid tissue lymphoma) have become curable, and others (gastric cancer) might be preventable with the application of H. pylori eradication therapy. Since its discovery, H. pylori has also been identified as a trigger for some extragastric diseases. Promising results in this exciting field might have a clinical effect in the near future. This Timeline gives an overview of the success of clinical research on H. pylori to date and highlights some future trends in this area.
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Affiliation(s)
- Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Leipziger Strasse 44, D-39120 Magdeburg, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Leipziger Strasse 44, D-39120 Magdeburg, Germany
| | - Michael Selgrad
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Leipziger Strasse 44, D-39120 Magdeburg, Germany
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Gonçalves IC, Henriques PC, Seabra CL, Martins MCL. The potential utility of chitosan micro/nanoparticles in the treatment of gastric infection. Expert Rev Anti Infect Ther 2014; 12:981-92. [DOI: 10.1586/14787210.2014.930663] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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35
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Fu HW. Helicobacter pylori neutrophil-activating protein: From molecular pathogenesis to clinical applications. World J Gastroenterol 2014; 20:5294-5301. [PMID: 24833859 PMCID: PMC4017044 DOI: 10.3748/wjg.v20.i18.5294] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 12/02/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) neutrophil-activating protein (HP-NAP) was originally identified as a virulence factor of H. pylori for its ability to activate neutrophils to generate respiratory burst by releasing reactive oxygen species. Later on, HP-NAP was also found to be involved in the protection of H. pylori from DNA damage, supporting the survival of H. pylori under oxidative stress. This protein is highly conserved and expressed by virtually all clinical isolates of H. pylori. The majority of patients infected with H. pylori produced antibodies specific for HP-NAP, suggesting its important role in immunity. In addition to acting as a pathogenic factor by activating the innate immunity through a wide range of human leukocytes, including neutrophils, monocytes, and mast cells, HP-NAP also mediates adaptive immunity through the induction of T helper cell type I responses. The pro-inflammatory and immunomodulatory properties of HP-NAP not only make it play an important role in disease pathogenesis but also make it a potential candidate for clinical use. Even though there is no convincing evidence to link HP-NAP to a disease outcome, recent findings supporting the pathogenic role of HP-NAP will be reviewed. In addition, the potential clinical applications of HP-NAP in vaccine development, clinical diagnosis, and drug development will be discussed.
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Hussain SA, Hamid S. Helicobacter pylori in humans: Where are we now? Adv Biomed Res 2014; 3:63. [PMID: 24627871 PMCID: PMC3950841 DOI: 10.4103/2277-9175.125844] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 11/06/2012] [Indexed: 01/01/2023] Open
Abstract
Helicobacter pylori has been associated with colonization of gastro duodenal mucosa of humans from millions of years. The main burden of the disese is in the developing countries, due to overcrowding and poor hygiene. If left untreated it leads to lot of sequlae from minor to sinister diseases over a period of time. The main challenges that remain are prevention of H. pylori-related diseases by effective treatment and screening procedures and development of a vaccine, which can address all these issues including beneficial aspects of H. pylori. The literature pertaining to different aspects of H. pylori were scrutinized from Pubmed. Material on clinical behavior, complications of chronic gastric involvement, and prevention besides role of H. pylori in nongastric diseases and the latest trends of management was collected for research and review. We continue to face many challenges. The prevention of cancer of the stomach, a worst sequlae of H. pylori continues to be a big challenge despite population screening and prevention surveys being underway in many countries. On the other hand continued scientific work has now unfolded involvement of H. pylori in extragastric diseases like cerebrovascular, cardiovascular, idiopathic thrombocytopenia, sideroblastic anemia, mental diseases, and collagen vascular diseases. In contrast, the beneficial effects of H. pylori with respect to allergic diseases and obesity are now clear. Moreover, problem of drug resistance for eradication of H. pylori has arisen for which novel treatments are being tried. Lactobacillus reuteri having anti H. pylori action is emerging as one of the promising treatment.
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Affiliation(s)
- Syed Arshad Hussain
- Department of Medicine (Endoscopy Unit) DHPulwama/Visiting Endoscopist, District Hospital, DHHandwara, Jammu and Kashmir, India
| | - Shamila Hamid
- Department of Community Medicine, SKIMS, Srinagar, Jammu and Kashmir, India
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Altman E, Chandan V, Harrison B. The potential of dextran-based glycoconjugates for development of Helicobacter pylori vaccine. Glycoconj J 2014; 31:13-24. [PMID: 23990317 DOI: 10.1007/s10719-013-9496-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Revised: 07/11/2013] [Accepted: 07/31/2013] [Indexed: 12/19/2022]
Abstract
We have recently demonstrated that synthetic glycoconjugates based on delipidated lipopolysaccharide (LPS) of Helicobacter pylori and containing an α(1-6)-glucan chain induced broadly cross-reactive functional antibodies in immunized animals. To investigate the candidacy of α(1-6)-glucan as an alternative vaccine strategy we prepared glycoconjugates based on dextrans produced by lactic acid bacteria Leuconostoc mesenteroides B512F and consisting of linear α(1-6)-glucan chains with limited branching. Three dextrans with averaged molecular masses of 5,000 Da, 3,500 Da and 1,500 Da, respectively, were modified with a diamino group-containing linker and conjugated to a carrier protein, tetanus toxoid (TT) or diphtheria toxoid (DT), and their immunological properties investigated. The conjugates were immunogenic in both rabbits and mice and induced specific IgG responses against α(1-6)-glucan-expressing H. pylori LPS. Studies performed with post-immune sera of mice and rabbits immunized with dextran-based conjugates demonstrated cross-reactivity with LPS from typeable and non-typeable strains of H. pylori and selected mutants. The post-immune sera from rabbits that received the conjugates exhibited functional activity against α(1-6)-glucan-positive strains of H. pylori. These data provide evidence that dextran-based conjugates may offer a simplified approach to the development of carbohydrate-based vaccines against H. pylori.
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Affiliation(s)
- Eleonora Altman
- National Research Council Canada, Ottawa, Ontario, K1A 0R6, Canada,
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39
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Fock KM, Graham DY, Malfertheiner P. Helicobacter pylori research: historical insights and future directions. Nat Rev Gastroenterol Hepatol 2013; 10:495-500. [PMID: 23752823 PMCID: PMC3973742 DOI: 10.1038/nrgastro.2013.96] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori leads to chronic gastritis, peptic ulcer disease and gastric cancer. With increasing issues of antibiotic resistance and changing epidemiology of this pathogen, new approaches are needed for effective management. In 1984, Dr Barry Marshall and Dr Robin Warren reported the association of Helicobacter pylori with peptic ulcers in The Lancet--a discovery that earned them the Nobel prize in Physiology or Medicine in 2005--but what progress have we made since then? Here, we have invited three international experts to give their insights into the advances in H. pylori research over the past 30 years and where research should be focused in the future.
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Affiliation(s)
| | - David Y. Graham
- Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard, Houston, TX377030, USA
| | - Peter Malfertheiner
- Otto-von-Guericke-Universtität, Leipziger Strasse 44, Magdeburg 39120, Germany
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40
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Selgrad M, Bornschein J, Malfertheiner P. Guidelines for treatment of Helicobacter pylori in the East and West. Expert Rev Anti Infect Ther 2013; 9:581-8. [PMID: 21819326 DOI: 10.1586/eri.11.80] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Infection with Helicobacter pylori remains a major healthcare burden, with persistently high prevalence rates, especially in less-developed countries. H. pylori infection is causally related to non-malignant and malignant gastroduodenal diseases, such as peptic ulcer diseases, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. Current international guidelines recommend a standard triple therapy as first-line therapy, including a proton pump inhibitor and a combination of amoxicillin and clarithromycin. Standard triple therapy has shown a decreasing efficacy over the years. The main reason is the increasing antibiotic resistance, particular to clarithromycin of H. pylori strains. Several new treatment options or modifications of already established regimens have been introduced to overcome treatment failure. In this article, we intend to report the reasons for treatment failure, and furthermore we give an overview of new treatment options as alternatives to the current treatment regimens. Finally, the strategy for the future is considered.
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Affiliation(s)
- Michael Selgrad
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
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41
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Every AL. Key host–pathogen interactions for designing novel interventions against Helicobacter pylori. Trends Microbiol 2013; 21:253-9. [DOI: 10.1016/j.tim.2013.02.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 02/17/2013] [Accepted: 02/25/2013] [Indexed: 01/08/2023]
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Chandan V, Jeremy AH, Dixon MF, Altman E, Crabtree JE. Colonization of gerbils withHelicobacter pyloriO-chain-deficient mutant SS1 HP0826::Kan results in gastritis and is associated withde novosynthesis of extended homopolymers. Pathog Dis 2013; 67:91-9. [DOI: 10.1111/2049-632x.12021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Revised: 12/05/2012] [Accepted: 12/28/2012] [Indexed: 01/05/2023] Open
Affiliation(s)
| | - Anthony H.T. Jeremy
- Leeds Institute of Molecular Medicine; St. James's University Hospital; Leeds; UK
| | | | | | - Jean E. Crabtree
- Leeds Institute of Molecular Medicine; St. James's University Hospital; Leeds; UK
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43
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44
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Haghighi MA, Mobarez AM, Salmanian AH, Moazeni M, Zali MR, Sadeghi M, Amani J. In silico experiment with an-antigen-toll like receptor-5 agonist fusion construct for immunogenic application to Helicobacter pylori. INDIAN JOURNAL OF HUMAN GENETICS 2013; 19:43-53. [PMID: 23901192 PMCID: PMC3722629 DOI: 10.4103/0971-6866.112885] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUNDS Helicobacter pylori colonize the gastric mucosa of half of the world's population. Although it is classified as a definitive type I carcinogen by World Health Organization, there is no effective vaccine against this bacterium. H. pylori evade the host immune response by avoiding toll-like detection, such as detection via toll-like receptor-5 (TLR-5). Thus, a chimeric construct consisting of selected epitopes from virulence factors that is incorporated into a TLR-5 ligand (Pseudomonas flagellin) could result in more potent innate and adaptive immune responses. MATERIALS AND METHODS Based on the histocompatibility antigens of BALB/c mice, in silico techniques were used to select several fragments from H. pylori virulence factors with a high density of B- and T-cell epitopes. RESULTS These segments consist of cytotoxin-associated geneA (residue 162-283), neutrophil activating protein (residue 30-135) and outer inflammatory protein A (residue 155-268). The secondary and tertiary structure of the chimeric constructs and other bioinformatics analyses such as stability, solubility, and antigenicity were performed. The chimeric construct containing antigenic segments of H. pylori proteins was fused with the D3 domain of Pseudomonas flagellin. This recombinant chimeric gene was optimized for expression in Escherichia coli. The in silico results showed that the conserved C- and N-terminal domains of flagellin and the antigenicity of selected fragments were retained. DISCUSSION In silico analysis showed that Pseudomonas flagellin is a suitable platform for incorporation of an antigenic construct from H. pylori. This strategy may be an effective tool for the control of H. pylori and other persistent infections.
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Affiliation(s)
- Mohamad Ali Haghighi
- Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ashraf Mohabati Mobarez
- Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Hatef Salmanian
- Department of Plant Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Mohamad Moazeni
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohamad Reza Zali
- Gastroenterology and Liver Disease Research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Sadeghi
- Department of Biochemistry National Institute of Genetic Engineering and Biotechnology, Baqiyatallah Medical Science University, Tehran, Iran
| | - Jafar Amani
- Applied Microbiology Research Center, Baqiyatallah Medical Science University, Tehran, Iran
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Li HB, Zhang JY, He YF, Chen L, Li B, Liu KY, Yang WC, Zhao Z, Zou QM, Wu C. Systemic immunization with an epitope-based vaccine elicits a Th1-biased response and provides protection against Helicobacter pylori in mice. Vaccine 2012; 31:120-6. [PMID: 23137845 DOI: 10.1016/j.vaccine.2012.10.091] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Revised: 10/09/2012] [Accepted: 10/25/2012] [Indexed: 12/12/2022]
Abstract
Vaccine-mediated Th1-biased CD4+ T cell responses have been shown to be crucial for protection against Helicobacter pylori (H. pylori). In this study, we investigated whether a vaccine composed of CD4+ T cell epitopes together with Th1 adjuvants could confer protection against H. pylori in a mouse model. We constructed an epitope-based vaccine, designated Epivac, which was composed of predicted immunodominant CD4+ T cell epitopes from H. pylori adhesin A (HpaA), urease B (UreB) and cytotoxin-associated gene A product (CagA). Together with four different Th1 adjuvants, Epivac was administered subcutaneously and the prophylactic potential was examined. Compared to non-immunized mice, immunization with Epivac alone or with a Th1 adjuvant significantly reduced H. pylori colonization, and better protection was observed when an adjuvant was used. Immunized mice exhibited a strong local and systemic Th1-biased immune response, which may contribute to the inhibition of H. pylori colonization. Though a significant specific antibody response was induced by the vaccine, no correlation was found between the intensity of the humoral response and the protective effect. Our results suggest that a vaccine containing CD4+ T cell epitopes is a promising candidate for protection against H. pylori infection.
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Affiliation(s)
- Hai-Bo Li
- Department of Clinical Microbiology and Immunology, College of Medical Laboratory, Third Military Medical University, Chongqing 400038, China
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Ulanova M, Tsang R, Altman E. Neglected infectious diseases in Aboriginal communities: Haemophilus influenzae serotype a and Helicobacter pylori. Vaccine 2012; 30:6960-6. [DOI: 10.1016/j.vaccine.2012.09.063] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Revised: 07/04/2012] [Accepted: 09/25/2012] [Indexed: 12/17/2022]
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Altman E, Chandan V, Harrison BA, Veloso-Pita R, Li J, KuoLee R, Chen W, Vérez-Bencomo V. Design and immunological properties of Helicobacter pylori glycoconjugates based on a truncated lipopolysaccharide lacking Lewis antigen and comprising an α-1,6-glucan chain. Vaccine 2012; 30:7332-41. [PMID: 22534169 DOI: 10.1016/j.vaccine.2012.04.035] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Revised: 03/02/2012] [Accepted: 04/10/2012] [Indexed: 12/16/2022]
Abstract
To investigate the vaccine potential of H. pylori lipopolysaccharide (LPS), truncated LPS of H. pylori strain 26695 HP0826::Kan lacking O-chain polysaccharide and comprising an extended α-1,6-linked glucan chain was conjugated to tetanus toxoid (TT) or bovine serum albumin (BSA). Two approaches were used for delipidation or partial delipidation of H. pylori LPS: (1) mild hydrolysis resulting in delipidated LPS (dLPS) and (2) treatment with anhydrous hydrazine resulting in removal of O-linked fatty acids (LPS-OH). Both LPS-OH and dLPS were covalently linked through a 2-keto-3-deoxy-octulosonic acid (Kdo) residue to a diamino group-containing spacer, followed by conjugation to thiolated TT or BSA to give conjugates LPS-OH-TT, dLPS-BSA and dLPS-TT, respectively. The LPS-OH-TT, dLPS-BSA and dLPS-TT conjugates were immunogenic in both rabbits and mice, inducing strong and specific IgG responses against homologous and heterologous strains of H. pylori. Moreover, the rabbit post-immune sera showed cross-reactivity against clinical isolates of H. pylori in a whole-cell indirect ELISA, which was further confirmed by indirect immunofluorescent microscopy. A tenfold stronger IgG immune response to the immunizing antigen was generated in mice and rabbits that received dLPS-containing conjugate. The post-immune sera of rabbits immunized with LPS-OH-TT, dLPS-BSA or dLPS-TT displayed significant bactericidal activity against mutant and wild-type α-1,6-glucan-expressing strains and selected clinical isolates of H. pylori. Finally, partial protection against H. pylori challenge was demonstrated in mice vaccinated with dLPS-TT conjugate adjuvanted with cholera toxin. In summary, this study shows that glycoconjugates based on delipidated or partially delipidated LPS from H. pylori 26695 HP0826::Kan mutant induce broadly cross-reactive functional antibodies in immunized animals and should be considered for further vaccine development and testing.
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Affiliation(s)
- Eleonora Altman
- Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario K1A 0R6, Canada.
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48
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Swain P. Future innovative therapies to treat upper gastrointestinal bleeding. Gastrointest Endosc Clin N Am 2011; 21:739-47. [PMID: 21944423 DOI: 10.1016/j.giec.2011.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The age of patients admitted to hospital for gastrointestinal bleeding will probably continue to rise, pushing the mortality rate upward, and the use of arthritic and blood thinning drugs will increase the incidence of gastrointestinal bleeding, especially in elderly patients. A slow decrease may be seen in the incidence of Helicobacter-induced ulceration and consequent bleeding in the west. New vaccine development has the best chance of reducing upper gastrointestinal bleeding worldwide, especially that caused by viral infections. Innovations in mechanical and compressive thermal hemostasis offer the best prospects for improvement in outcome from flexible therapeutic endoscopy.
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Affiliation(s)
- Paul Swain
- Department of Surgery and Cancer, Imperial College, St Mary's Hospital, London, UK.
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50
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Bornschein J, Malfertheiner P. Gastric carcinogenesis. Langenbecks Arch Surg 2011; 396:729-42. [PMID: 21611816 DOI: 10.1007/s00423-011-0810-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Accepted: 05/09/2011] [Indexed: 02/07/2023]
Abstract
INTRODUCTION In most patients, gastric cancer is diagnosed in advanced stage. Curative treatment options are limited and the mortality is high. The process of gastric carcinogenesis is triggered by Helicobacter pylori-driven gastritis and is further characterized by its complexity of interaction with other risk factors. Health care systems are challenged for the improvement of prevention, early diagnosis, and effective treatments. METHODS An extensive literature research has been performed to elucidate the interplay between etiological factors involved in gastric carcinogenesis. RESULTS H. pylori is the most important carcinogen for gastric adenocarcinoma. Evidence is provided by experiments including animal studies as well as clinical observational and interventional studies in humans. Eradication has the potential to prevent gastric cancer and offers the greatest benefit if performed before premalignant changes of the gastric mucosa have occurred. Bacterial virulence factors are essential players in modulating the immune response involved in the initiation of the carcinogenesis in the stomach. Host genetic factors contribute to the regulation of the inflammatory response and in the aggravation of mucosal damage. The harmful role of environmental factors is restricted to salt intake and smoking of tobacco. The ingestion of fruit and vegetables has some protective effect. CONCLUSION Infection with H. pylori is the major risk factor for gastric cancer development, and thus, eradication of the Helicobacter offers a promising best option for prevention of the disease. Bacterial virulence, host genetic factors, and environmental influences are interacting in the multifactorial process of gastric carcinogenesis.
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Affiliation(s)
- Jan Bornschein
- Department of Gastroenterology, Hepatology & Infectious Diseases, Otto-von-Guericke University of Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
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