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1
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Patil S, Yu S, Jobby R, Ravichandran V, Sarkar S. A critical review on In Vivo and Ex Vivo models for the investigation of Helicobacter pylori infection. Front Cell Infect Microbiol 2025; 15:1516237. [PMID: 40438238 PMCID: PMC12116454 DOI: 10.3389/fcimb.2025.1516237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 04/21/2025] [Indexed: 06/01/2025] Open
Abstract
Helicobacter pylori is a stomach-dwelling bacterium with a crude global prevalence of nearly 45% in adults and 35% in children and adolescents. Chronic H. pylori infection and the resulting inflammation are major causes of gastritis, peptic ulcer disease and gastric cancer. Since its discovery in 1982, various animal models have been proposed to recreate the specific pathophysiological interactions between H. pylori and the human host. These infection models have been instrumental in dissecting the key drivers of H. pylori colonization, persistence and mediators of host immune responses. However, a comprehensive understanding of the molecular triggers for malignant transformation of the gastric mucosa is still lacking. Vaccine development in this area has stalled, as promising candidates identified through animal studies have failed in advanced human clinical trials. Currently, H. pylori eradication is heavily reliant on different antimicrobial agents. As with other bacterial pathogens, the growing antimicrobial resistance in H. pylori remains a major challenge, making eradication therapy increasingly complex and prolonged, over time. Recent drug approvals have mostly been for newer combinations of conventional antibiotics and proton pump inhibitors. Thus, the development of novel treatments and innovative models are crucial for advancing the drug development pipeline. This review encompasses the development and recent advances in animal and non-animal models of H. pylori gastric infection and its applications in investigating novel therapeutics and vaccine candidates.
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Affiliation(s)
- Shwetlaxmi Patil
- Amity Institute of Biotechnology, Amity University Maharashtra, Mumbai, India
| | - Songmin Yu
- Murdoch Children’s Research Institute, Parkville, VIC, Australia
- Department of Pediatrics, University of Melbourne, Parkville, VIC, Australia
| | - Renitta Jobby
- Amity Institute of Biotechnology, Amity University Maharashtra, Mumbai, India
- Amity Centre of Excellence in Astrobiology, Amity University Maharashtra, Mumbai, India
| | - Vinothkannan Ravichandran
- Amity Institute of Biotechnology, Amity University Maharashtra, Mumbai, India
- Center for Drug Discovery and Development (CD3), Amity Institute of Biotechnology, Amity University Maharashtra, Mumbai, India
| | - Sohinee Sarkar
- Murdoch Children’s Research Institute, Parkville, VIC, Australia
- Department of Pediatrics, University of Melbourne, Parkville, VIC, Australia
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2
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Zhang Y, Xu C, Zhong HM, Song Y, Luo H, Liu P. H. pylori infection downregulates the expression and release of miR- 223 in neutrophils. Int Microbiol 2025:10.1007/s10123-025-00660-9. [PMID: 40210833 DOI: 10.1007/s10123-025-00660-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 02/21/2025] [Accepted: 04/04/2025] [Indexed: 04/12/2025]
Abstract
OBJECTIVE This study aimed to investigate the association between serum miR- 223 concentration and Helicobacter pylori (H. pylori) infection. METHODS H. pylori status was assessed using the Urea 13C Breath Test Kit and Typing Detection Kit for antibodies against H. pylori. Patients were considered positive for H. pylori infection when both tests yielded positive results. Serum miRNAs were extracted using the miRNeasy Mini Kit, and quantitative real-time PCR was performed to analyze the relative expression level of miR- 223. RESULTS We found that the relative expression level of miR- 223 in neutrophils from H. pylori-positive patients (20.35 ± 5.85) was significantly lower than that from healthy individuals (45.92 ± 10.59) (p < 0.05). Moreover, the expression level of miR- 7, which we selected as a control molecule, was not significantly lower in neutrophils from H. pylori-positive patients (3.07 ± 0.78) than healthy controls (4.43 ± 1.57) (p > 0.05), and the expression of miR- 7 was lower than miR- 223. CONCLUSION These results indicated that circulating miR- 223 down-expression was of neutrophil origin in vitro and inversely associated with H. pylori infection.
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Affiliation(s)
- Yu Zhang
- College of Medical Laboratory, Dalian Medical University, Dalian, Liaoning, 116044, PR China
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China
- Department of Laboratory Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650118, PR China
| | - Chang Xu
- College of Medical Laboratory, Dalian Medical University, Dalian, Liaoning, 116044, PR China
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China
| | - Hao-Ming Zhong
- School of Basic Medical Sciences, Shandong University, Jinan, Shandong, 250012, PR China
| | - Yu Song
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China
- Marine College, Shandong University, Weihai, Shandong, 264209, PR China
| | - Hong Luo
- College of Medical Laboratory, Dalian Medical University, Dalian, Liaoning, 116044, PR China
| | - Peng Liu
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China.
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3
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Li Y, Farhan MHR, Yang X, Guo Y, Sui Y, Chu J, Huang L, Cheng G. A review on the development of bacterial multi-epitope recombinant protein vaccines via reverse vaccinology. Int J Biol Macromol 2024; 282:136827. [PMID: 39476887 DOI: 10.1016/j.ijbiomac.2024.136827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 10/04/2024] [Accepted: 10/21/2024] [Indexed: 11/10/2024]
Abstract
Bacterial vaccines play a crucial role in combating bacterial infectious diseases. Apart from the prevention of disease, bacterial vaccines also help to reduce the mortality rates in infected populations. Advancements in vaccine development technologies have addressed the constraints of traditional vaccine design, providing novel approaches for the development of next-generation vaccines. Advancements in reverse vaccinology, bioinformatics, and comparative proteomics have opened horizons in vaccine development. Specifically, the use of protein structural data in crafting multi-epitope vaccines (MEVs) to target pathogens has become an important research focus in vaccinology. In this review, we focused on describing the methodologies and tools for epitope vaccine development, along with recent progress in this field. Moreover, this article also discusses the challenges in epitope vaccine development, providing insights for the future development of bacterial multi-epitope genetically engineered vaccines.
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Affiliation(s)
- Yuxin Li
- National Reference Laboratory of Veterinary Drug Residues (HZAU), Huazhong Agricultural University, Wuhan, Hubei 430070, PR China
| | - Muhammad Haris Raza Farhan
- National Reference Laboratory of Veterinary Drug Residues (HZAU), Huazhong Agricultural University, Wuhan, Hubei 430070, PR China
| | - Xiaohan Yang
- National Reference Laboratory of Veterinary Drug Residues (HZAU), Huazhong Agricultural University, Wuhan, Hubei 430070, PR China
| | - Ying Guo
- National Reference Laboratory of Veterinary Drug Residues (HZAU), Huazhong Agricultural University, Wuhan, Hubei 430070, PR China
| | - Yuxin Sui
- National Reference Laboratory of Veterinary Drug Residues (HZAU), Huazhong Agricultural University, Wuhan, Hubei 430070, PR China
| | - Jinhua Chu
- National Reference Laboratory of Veterinary Drug Residues (HZAU), Huazhong Agricultural University, Wuhan, Hubei 430070, PR China
| | - Lingli Huang
- National Reference Laboratory of Veterinary Drug Residues (HZAU), Huazhong Agricultural University, Wuhan, Hubei 430070, PR China; MOA Laboratory of Risk Assessment for Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, PR China
| | - Guyue Cheng
- National Reference Laboratory of Veterinary Drug Residues (HZAU), Huazhong Agricultural University, Wuhan, Hubei 430070, PR China; MOA Laboratory of Risk Assessment for Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, PR China.
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4
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Amalia R, Panenggak NSR, Doohan D, Rezkitha YAA, Waskito LA, Syam AF, Lubis M, Yamaoka Y, Miftahussurur M. A comprehensive evaluation of an animal model for Helicobacter pylori-associated stomach cancer: Fact and controversy. Helicobacter 2023; 28:e12943. [PMID: 36627714 DOI: 10.1111/hel.12943] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 11/22/2022] [Accepted: 11/22/2022] [Indexed: 01/12/2023]
Abstract
Even though Helicobacter pylori infection was the most causative factor of gastric cancer, numerous in vivo studies failed to induce gastric cancer using H. pylori infection only. The utilization of established animal studies in cancer research is crucial as they aim to investigate the coincidental association between suspected oncogenes and pathogenesis as well as generate models for the development and testing of potential treatments. The methods to establish gastric cancer using infected animal models remain limited, diverse in methods, and showed different results. This study investigates the differences in animal models, which highlight different pathological results in gaster by literature research. Electronic databases searched were performed in PubMed, Science Direct, and Cochrane, without a period filter. A total of 135 articles were used in this study after a full-text assessment was conducted. The most frequent animal models used for gastric cancer were Mice, while Mongolian gerbils and Transgenic mice were the most susceptible model for gastric cancer associated with H. pylori infection. Additionally, transgenic mice showed that the susceptibility to gastric cancer progression was due to genetic and epigenetic factors. These studies showed that in Mongolian gerbil models, H. pylori could function as a single agent to trigger stomach cancer. However, most gastric cancer susceptibilities were not solely relying on H. pylori infection, and numerous factors are involved in cancer progression. Further study using Mongolian gerbils and Transgenic mice is crucial to conduct and establish the best models for gastric cancer associated H. pylori.
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Affiliation(s)
- Rizki Amalia
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Nur Syahadati Retno Panenggak
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Dalla Doohan
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Anatomy, Histology and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Yudith Annisa Ayu Rezkitha
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Internal Medicine, Faculty of Medicine, Universitas Muhammadiyah Surabaya, Surabaya, Indonesia
| | - Langgeng Agung Waskito
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Ari Fahrial Syam
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Masrul Lubis
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan.,Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Texas, Houston, USA
| | - Muhammad Miftahussurur
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, Indonesia
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5
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Sun P, Li X, Pan C, Liu Z, Wu J, Wang H, Zhu L. A Short Peptide of Autotransporter Ata Is a Promising Protective Antigen for Vaccination Against Acinetobacter baumannii. Front Immunol 2022; 13:884555. [PMID: 35493470 PMCID: PMC9043751 DOI: 10.3389/fimmu.2022.884555] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 03/21/2022] [Indexed: 11/25/2022] Open
Abstract
With the emergence of multidrug-resistant strains, Acinetobacter baumannii infection is becoming a thorny health problem in hospitals. However, there are no licensed vaccines against A. baumannii. Acinetobacter trimeric autotransporter (Ata) is an important known virulence factor located on the outer membrane of bacteria. Herein, we carried out a series of experiments to test the immunogenicity of a short C-terminal extracellular region of Ata (Ataα, only containing 39 amino acids) in a murine model. The short peptide Ataα was fused with the cholera toxin B subunit (CTB), which has been reported to have immunoadjuvant activity. The fusion protein showed no inflammation and organ damages, and have the ability to elicit both Th1 and Th2 immune responses in mice. The bactericidal activities against A. baumannii and prophylactic effects of the fusion protein were further evidenced by a significant reduction in the bacterial load in the organs and blood. In addition, the candidate vaccine could provide broad protection against lethal challenges with a variety of A. baumannii strains. Moreover, when CpG was added on the basis of aluminum adjuvant, the immune response, especially cellular immunity, could be further strengthened. Overall, these results revealed that the Ataα is a promising vaccine target against A. baumannii infection.
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Affiliation(s)
- Peng Sun
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China
- School of Medicine, Tsinghua University, Beijing, China
| | - Xin Li
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Chao Pan
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China
| | - Zhicheng Liu
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China
| | - Jun Wu
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China
| | - Hengliang Wang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China
- School of Medicine, Tsinghua University, Beijing, China
| | - Li Zhu
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China
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6
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Construction of Orthogonal Modular Proteinaceous Nanovaccine Delivery Vectors Based on mSA-Biotin Binding. NANOMATERIALS 2022; 12:nano12050734. [PMID: 35269221 PMCID: PMC8911943 DOI: 10.3390/nano12050734] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/16/2022] [Accepted: 02/19/2022] [Indexed: 12/16/2022]
Abstract
Proteinaceous nanovaccine delivery systems have significantly promoted the development of various high-efficiency vaccines. However, the widely used method of coupling the expression of scaffolds and antigens may result in their structural interference with each other. Monovalent streptavidin (mSA) is a short monomer sequence, which has a strong affinity for biotin. Here, we discuss an orthogonal, modular, and highly versatile self-assembled proteinaceous nanoparticle chassis that facilitates combinations with various antigen cargos by using mSA and biotin to produce nanovaccines. We first improved the yield of these nanoparticles by appending a short sugar chain on their surfaces in a constructed host strain. After confirming the strong ability to induce both Th1- and Th2-mediated immune responses based on the plasma cytokine spectrum from immunized mice, we further verified the binding ability of biotinylated nanoparticles to mSA-antigens. These results demonstrate that our biotinylated nanoparticle chassis could load both protein and polysaccharide antigens containing mSA at a high affinity. Our approach thus offers an attractive technology for combining nanoparticles and antigen cargos to generate various high-performance nanovaccines. In particular, the designed mSA connector (mSA containing glycosylation modification sequences) could couple with polysaccharide antigens, providing a new attractive strategy to prepare nanoscale conjugate vaccines.
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7
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Mohammadzadeh R, Soleimanpour S, Pishdadian A, Farsiani H. Designing and development of epitope-based vaccines against Helicobacter pylori. Crit Rev Microbiol 2021; 48:489-512. [PMID: 34559599 DOI: 10.1080/1040841x.2021.1979934] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori infection is the principal cause of serious diseases (e.g. gastric cancer and peptic ulcers). Antibiotic therapy is an inadequate strategy in H. pylori eradication because of which vaccination is an inevitable approach. Despite the presence of countless vaccine candidates, current vaccines in clinical trials have performed with poor efficacy which makes vaccination extremely challenging. Remarkable advancements in immunology and pathogenic biology have provided an appropriate opportunity to develop various epitope-based vaccines. The fusion of proper antigens involved in different aspects of H. pylori colonization and pathogenesis as well as peptide linkers and built-in adjuvants results in producing epitope-based vaccines with excellent therapeutic efficacy and negligible adverse effects. Difficulties of the in vitro culture of H. pylori, high genetic variation, and unfavourable immune responses against feeble epitopes in the complete antigen are major drawbacks of current vaccine strategies that epitope-based vaccines may overcome. Besides decreasing the biohazard risk, designing precise formulations, saving time and cost, and induction of maximum immunity with minimum adverse effects are the advantages of epitope-based vaccines. The present article is a comprehensive review of strategies for designing and developing epitope-based vaccines to provide insights into the innovative vaccination against H. pylori.
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Affiliation(s)
- Roghayeh Mohammadzadeh
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saman Soleimanpour
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Reference Tuberculosis Laboratory, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abbas Pishdadian
- Department of Immunology, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Hadi Farsiani
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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8
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Dos Santos Viana I, Cordeiro Santos ML, Santos Marques H, Lima de Souza Gonçalves V, Bittencourt de Brito B, França da Silva FA, Oliveira E Silva N, Dantas Pinheiro F, Fernandes Teixeira A, Tanajura Costa D, Oliveira Souza B, Lima Souza C, Vasconcelos Oliveira M, Freire de Melo F. Vaccine development against Helicobacter pylori: from ideal antigens to the current landscape. Expert Rev Vaccines 2021; 20:989-999. [PMID: 34139141 DOI: 10.1080/14760584.2021.1945450] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 06/16/2021] [Indexed: 12/19/2022]
Abstract
Introduction: The interest of the world scientific community for an effective vaccine against Helicobacter pylori infection arises from its high prevalence and association with many diseases. Moreover, with an immunological response that is not always effective for the eradication of the bacteria and an increasing antibiotic resistance in the treatment of this infection, the search for a vaccine and new therapeutic modalities to control this infection is urgent.Areas covered: We bring an overview of the infection worldwide, discussing its prevalence, increasing resistance to antibiotics used in its therapy, in addition to the response of the immune system to the infection registered so far. Moreover, we address the most used antigens and their respective immunological responses expected or registered up to now. Finally, we address the trials and their partial results in development for such vaccines.Expert opinion: Although several studies for the development of an effective vaccine against this pathogen are taking place, many are still in the preclinical phase or even without updated information. In this sense, taking into account the high prevalence and association with important comorbidities, the interest of the pharmaceutical industry in developing an effective vaccine against this pathogen is questioned.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Davi Tanajura Costa
- Instituto Multidisciplinar Em Saúde, Universidade Federal da Bahia, Bahia, Brazil
| | - Briza Oliveira Souza
- Instituto Multidisciplinar Em Saúde, Universidade Federal da Bahia, Bahia, Brazil
| | - Cláudio Lima Souza
- Instituto Multidisciplinar Em Saúde, Universidade Federal da Bahia, Bahia, Brazil
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Wu J, Zhu X, Guo X, Yang Z, Cai Q, Gu D, Luo W, Yuan C, Xiang Y. Helicobacter urease suppresses cytotoxic CD8 + T cell responses through activating Myh9-dependent induction of PD-L1. Int Immunol 2021; 33:491-504. [PMID: 34297096 DOI: 10.1093/intimm/dxab044] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 07/23/2021] [Indexed: 11/14/2022] Open
Abstract
As a key virulence factor for persistent colonization, Urease B subunit (UreB) is considered to be an ideal vaccine antigen against Helicobacter pylori (H. pylori) infection. However, the role and molecular mechanisms of UreB involved in immune microenvironment dysregulation still remains largely unknown. In the present study, we evaluated the effects of UreB on macrophage activation and found that UreB induced PD-L1 accumulation on Bone marrow-derived macrophages (BMDMs). Co-culture assays further revealed that UreB-induced PD-L1 expression on BMDMs significantly decreased the proliferation and secretion of cytolytic molecules (granzyme B and perforin) of splenic CD8 + T cells isolated from inactivated H. pylori-immunized mice. More importantly, myosin heavy chain 9 (Myh9) was confirmed to be a direct membrane receptor of UreB via using LC-MS/MS and Co-immunoprecipitation and required for PD-L1 upregulation on BMDMs. Molecular studies further demonstrated that the interaction between UreB and Myh9 decreased GCN2 autophosphorylation and enhanced intracellular pool of amino acids, leading to the upregulation of S6K phosphorylation, a commonly used marker for monitoring activation of mTORC1 signaling activity. Furthermore, blocking mTORC1 activation with its inhibitor Temsirolimus reversed UreB-induced PD-L1 upregulation and the subsequently inhibitory effects of BMDMs on activation of cytotoxic CD8 + T cell responses. Overall, our data unveil a novel immunosuppressive mechanism of UreB during H. pylori infection, which may provide valuable clue for the optimization of H. pylori vaccine.
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Affiliation(s)
- Jian Wu
- Department of Laboratory Medicine, Wuhan Medical and Health Center for Women and Children, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, P.R. China
| | - Xiaowen Zhu
- Department of Gastroenterology, Affiliated Taihe Hospital of Hubei university of Medicine, Shiyan 442099, P.R. China
| | - Xia Guo
- Department of Laboratory Medicine, Wuhan Medical and Health Center for Women and Children, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, P.R. China
| | - Ze Yang
- Blood Transfusion Department, The Second Affiliated Hospital of Shandong First Medical University, Taian 271000, P.R. China
| | - Qinzhen Cai
- Department of Laboratory Medicine, Wuhan Medical and Health Center for Women and Children, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, P.R. China
| | - Dongmei Gu
- Department of Clinical Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Wei Luo
- Department of Clinical Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Chunhui Yuan
- Department of Laboratory Medicine, Wuhan Medical and Health Center for Women and Children, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, P.R. China
| | - Yun Xiang
- Department of Laboratory Medicine, Wuhan Medical and Health Center for Women and Children, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, P.R. China
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10
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Xie W, Zhao W, Zou Z, Kong L, Yang L. Oral multivalent epitope vaccine, based on UreB, HpaA, CAT, and LTB, for prevention and treatment of Helicobacter pylori infection in C57BL / 6 mice. Helicobacter 2021; 26:e12807. [PMID: 33847026 DOI: 10.1111/hel.12807] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 03/19/2021] [Accepted: 03/26/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND As the resistance of Helicobacter pylori to traditional triple therapy is gradually revealed, an increasing number of people are focusing on vaccine treatments for H. pylori infection. Epitope vaccines are a promising strategy for the treatment of H. pylori infection, and multivalent vaccines will be more effective than monovalent vaccines. MATERIALS AND METHODS In this study, we designed a multivalent vaccine named LHUC, which consists of the adjuvant LTB as well as three Th cell epitopes (HpaA154-171 , UreB237-251, and UreB546-561 ) and five B-cell epitopes (UreB349-363 , UreB327-334 , CAT394-405 , CAT387-397, and HpaA132-141 ) from UreB, HpaA, and catalase. In BALB/c mice, the specificity and immunogenicity of the fusion peptide LHUC and the neutralization of H. pylori urease and catalase by the specific IgG elicited by LHUC were evaluated. The preventive and therapeutic effects of LHUC were evaluated in C57BL/6 mice infected with H. pylori. RESULTS The results showed that compared with LTB and PBS, LHUC induced specific IgG and IgA antibody production in mice, and IgG antibodies significantly inhibited the H. pylori urease and catalase activities in vitro. Additionally, by detecting the levels of IFN-γ, IL-4, and IL-17 in lymphocyte supernatants, we proved that LHUC could activate Th1, Th2, and Th17 mixed T-cell immune responses in vivo. Finally, a C57BL/6 mouse model of gastric infection with H. pylori was established. The results showed that compared with the effects of LTB and PBS, the prevention and treatment effects of oral inoculation with LHUC significantly inhibited bacterial colonization. CONCLUSIONS In conclusion, LHUC, a multivalent vaccine based on multiple H. pylori antigens, is a promising and safe vaccine that can effectively reduce the colonization of H. pylori in the stomach.
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Affiliation(s)
- Wenwei Xie
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
| | - Wenfeng Zhao
- Department of Biochemistry, China Pharmaceutical university, Nanjing, China
| | - Ziling Zou
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
| | - Lingyi Kong
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
| | - Lei Yang
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
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11
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Guo L, Hong D, Wang S, Zhang F, Tang F, Wu T, Chu Y, Liu H, He M, Yang H, Yin R, Liu K. Therapeutic Protection Against H. pylori Infection in Mongolian Gerbils by Oral Immunization With a Tetravalent Epitope-Based Vaccine With Polysaccharide Adjuvant. Front Immunol 2019; 10:1185. [PMID: 31191547 PMCID: PMC6546824 DOI: 10.3389/fimmu.2019.01185] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 05/09/2019] [Indexed: 12/28/2022] Open
Abstract
Urease is an effective target for design of a therapeutic epitope vaccine against Helicobacter pylori (H. pylori). In our previous studies, an epitope vaccine CTB-UE containing Th and B epitopes from H. pylori urease was constructed, and the CTB-UE vaccine could provide therapeutic effect on H. pylori infection in mice. However, a multivalent vaccine, combining different antigens participating in different aspects of H. pylori colonization and pathogenesis, may be more effective as a therapeutic vaccine than a univalent vaccine targetting urease. Therefore, a multivalent epitope vaccine FVpE, containing Th1-type immune adjuvant NAP, three selected functional fragments from CagA and VacA, and an urease multi-epitope peptide (UE) from CTB-UE, was constructed in this study and expected to obtain better sterilizing immunity than the univalent epitope vaccine CTB-UE. The therapeutic effect of multivalent epitope vaccine FVpE with polysaccharide adjuvant (PA) was evaluated in H. pylori-infected Mongolian gerbil model. The results showed that both FvpE and CTB-UE vaccine could induce similar levels of specific antibodies against H. pylori urease, and had similar inhibition effect on H. pylori urease activity. However, only FVpE could induce high levels of specific antibodies to CagA, VacA, and NAP. In addition, oral therapeutic immunization with FVpE plus PA significantly reduced the number of H. pylori colonies in the stomach of Mongolian gerbils compared with oral immunization with CTB-UE plus PA, or FVpE only, and the FVpE vaccine with PA even exhibited sterilizing immunity. The protection of FVpE was related to the mixed CD4+ T cell responses and epitope-specific antibodies against various H. pylori antigens. These results indicate that a multivalent epitope vaccine targetting various H. pylori antigens could be a promising candidate against H. pylori infection.
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Affiliation(s)
- Le Guo
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, China.,Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, China.,Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Dantong Hong
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Shue Wang
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Fan Zhang
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Feng Tang
- Research Center for High Altitude Medicine, Qinghai University, Xining, China
| | - Tao Wu
- Clinical Laboratory, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
| | - Yuankui Chu
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Hongpeng Liu
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Meng He
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Hua Yang
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Runting Yin
- Center for Cell Therapy, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Kunmei Liu
- Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, China.,Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
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12
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Luo S, Liu W, Zeng Z, Ye F, Hu C, Xu N, Huang A, Xi T, Xing Y. Toxic adjuvants alter the function and phenotype of dendritic cells to initiate adaptive immune responses induced by oral Helicobacter pylori vaccines. Helicobacter 2018; 23:e12536. [PMID: 30247802 DOI: 10.1111/hel.12536] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 07/26/2018] [Accepted: 07/27/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Toxic adjuvant is considered as an indispensable constituent for oral Helicobacter pylori (H. pylori) vaccines. However, the elaborate role of toxic adjuvant in the initiation of adaptive immune response is largely undescribed. MATERIALS AND METHODS We employed an acid-resistant HP55/PLGA nanoparticles (NPs) delivery system encapsulating three antigens (Hsp, Nap, and Lpp20) from H. pylori and accompanied with three adjuvants (LPS, CpG, and chimeric flagellum (CF)) to explore the underlying mechanism of the adjuvant constituent. H. pylori-specific antibody responses were detected by ELISA. Gastric inflammatory and Th1/Th17 responses were analyzed by flow cytometry. Expressions of inflammatory cytokines were measured by quantitative real-time PCR. RESULTS In bone marrow-derived dendritic cells' (BMDCs) model, the addition of toxic adjuvants is responsible for the proinflammatory function, but not the mature phenotype of BMDCs. In vivo, intestinal loop injection with NPs + LPS, rather than NPs alone, altered the dendritic cell (DC) phenotypes in mesenteric lymph nodes and drove a local proinflammatory microenvironment. In a prophylactic vaccination model, mice immunized with NPs + adjuvants significantly reduced the gastric colonization of H. pylori, induced antigen-specific antibody responses and Th1/Th17 cell responses. After H. pylori challenge, these mice showed potent recall responses involving both neutrophil and inflammatory monocyte infiltration. Additionally, TLR4 knockout mice were immunized with NPs + LPS and NPs + CF, respectively; only the recipients of NPs + CF orchestrated a protective response to control bacterial infection. CONCLUSIONS Our study indicated that toxic adjuvants within oral H.pylori vaccines altered the function and phenotype of dendritic cells and facilitated the establishment of proinflammatory microenvironment to initiate adaptive immune responses.
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Affiliation(s)
- Shuanghui Luo
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Wei Liu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Zhiqin Zeng
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Feng Ye
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chupeng Hu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Ningyin Xu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - An Huang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Tao Xi
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.,Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Yingying Xing
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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13
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Ghasemi A, Mohammad N, Mautner J, Taghipour Karsabet M, Amani J, Ardjmand A, Vakili Z. Immunization with a recombinant fusion protein protects mice against Helicobacter pylori infection. Vaccine 2018; 36:5124-5132. [PMID: 30041879 DOI: 10.1016/j.vaccine.2018.07.033] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 07/10/2018] [Accepted: 07/16/2018] [Indexed: 02/07/2023]
Abstract
More than 50% of the world's population is infected with the bacterium Helicobacter pylori. If left untreated, infection with H. pylori can cause chronic gastritis and peptic ulcer disease, which may progress into gastric cancer. Owing to the limited efficacy of anti-H. pylori antibiotic therapy in clinical practice, the development of a protective vaccine to combat this pathogen has been a tempting goal for several years. In this study, a chimeric gene coding for the antigenic parts of H. pylori FliD, UreB, VacA, and CagL was generated and expressed in bacteria and the potential of the resulting fusion protein (rFUVL) to induce humoral and cellular immune responses and to provide protection against H. pylori infection was evaluated in mice. Three different immunization adjuvants were tested along with rFUVL: CpG oligodeoxynucleotides (CpG ODN), Addavax, and Cholera toxin subunit B. Compared to the control group that had received PBS, vaccinated mice showed significantly higher cellular recall responses and antigen-specific IgG2a, IgG1, and gastric IgA antibody titers. Importantly, rFUVL immunized mice exhibited a reduction of about three orders of magnitude in their stomach bacterial loads. Thus, adjuvanted rFUVL might be considered as a promising vaccine candidate for the control of H. pylori infection.
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Affiliation(s)
- Amir Ghasemi
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Department of Infectious Disease and Immunology, College of Veterinary Medicine, University of Florida, FL, USA.
| | - Nazanin Mohammad
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Josef Mautner
- Technische Universität München & Helmholtz Zentrum München, Munich, Germany
| | - Mehrnaz Taghipour Karsabet
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Jafar Amani
- Applied Microbiology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Abolfazl Ardjmand
- Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Zarichehr Vakili
- Department of Pathology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
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14
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Immunization with recombinant FliD confers protection against Helicobacter pylori infection in mice. Mol Immunol 2018; 94:176-182. [DOI: 10.1016/j.molimm.2018.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 11/27/2017] [Accepted: 01/04/2018] [Indexed: 12/23/2022]
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15
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16
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Keck J, Gupta R, Christenson LK, Arulanandam BP. MicroRNA mediated regulation of immunity against gram-negative bacteria. Int Rev Immunol 2017; 36:287-299. [PMID: 28800263 PMCID: PMC6904929 DOI: 10.1080/08830185.2017.1347649] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Evidence over the last couple decades has comprehensively established that short, highly conserved, non-coding RNA species called microRNA (miRNA) exhibit the ability to regulate expression and function of host genes at the messenger RNA (mRNA) level. MicroRNAs play key regulatory roles in immune cell development, differentiation, and protective function. Intrinsic host immune response to invading pathogens rely on intricate orchestrated events in the development of innate and adaptive arms of immunity. We discuss the involvement of miRNAs in regulating these processes against gram negative pathogens in this review.
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Affiliation(s)
- Jonathon Keck
- South Texas Center for Emerging Infectious Diseases and Center of Excellence in Infection Genomics, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249
| | - Rishein Gupta
- South Texas Center for Emerging Infectious Diseases and Center of Excellence in Infection Genomics, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249
| | - Lane K. Christenson
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Bernard P. Arulanandam
- South Texas Center for Emerging Infectious Diseases and Center of Excellence in Infection Genomics, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249
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17
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Tan Z, Liu W, Liu H, Li C, Zhang Y, Meng X, Tang T, Xi T, Xing Y. Oral Helicobacter pylori vaccine-encapsulated acid-resistant HP55/PLGA nanoparticles promote immune protection. Eur J Pharm Biopharm 2017; 111:33-43. [DOI: 10.1016/j.ejpb.2016.11.007] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Accepted: 11/02/2016] [Indexed: 12/19/2022]
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18
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Talebi Bezmin Abadi A, Lee YY. Chinese Helicobacter pylori vaccine: Solution for an old challenge? World J Gastrointest Pharmacol Ther 2016; 7:412-415. [PMID: 27602242 PMCID: PMC4986397 DOI: 10.4292/wjgpt.v7.i3.412] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 04/09/2016] [Accepted: 05/17/2016] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori (H. pylori) is an important cause for gastric cancer in high risk individuals. H. pylori colonizes more than 50% of the world's population and associated peptic ulcer disease and gastric malignancy have important public health implications. It has been classified as a class I carcinogen in 1994 by the World Health Organization. Clinicians are often prompted to eliminate the infection the moment it is detected. This also, unfortunately, led to reckless use of antibiotics and reports of increasing resistance are now worldwide. Each year, many of people die from gastric cancer; thus application of effective vaccine can reduce this relatively high mortality worldwide. H. pylori can be eliminated by antibiotics but efficacy is sharply decreasing. Moreover, current therapy is also expensive and with side effects. Vaccine may be the best solution to the above problem but there are many challenges in producing such an effective therapeutic vaccine. Recently, the Chinese group published in Lancet, a single-center, randomized, phase III study of an oral recombinant vaccine (Urease B subunit fused with heat-labile enterotoxin B derived from Escherichia coli) prescribed in the Chinese children (6-15 years) without a history of H. pylori infection. This review provides an insight into this new solution for an old challenge.
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19
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Li Y, Chen Z, Ye J, Ning L, Luo J, Zhang L, Jiang Y, Xi Y, Ning Y. Antibody Production and Th1-biased Response Induced by an Epitope Vaccine Composed of Cholera Toxin B Unit and Helicobacter pylori Lpp20 Epitopes. Helicobacter 2016; 21:234-48. [PMID: 26332255 DOI: 10.1111/hel.12268] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND The epitope vaccine is an attractive potential for prophylactic and therapeutic vaccination against Helicobacter pylori (H. pylori) infection. Lpp20 is one of major protective antigens which trigger immune response after H. pylori invades host and has been considered as an excellent vaccine candidate for the control of H. pylori infection. In our previous study, one B-cell epitope and two CD4(+) T-cell epitopes of Lpp20 were identified. OBJECTIVE In this study, an epitope vaccine composed of mucosal adjuvant cholera toxin B subunit (CTB) and these three identified Lpp20 epitopes were constructed to investigate the efficacy of this epitope vaccine in mice. METHODS The epitope vaccine including CTB, one B-cell, and two CD4(+) T-cell epitopes of Lpp20 was constructed and named CTB-Lpp20, which was then expressed in Escherichia coli and used for intraperitoneal immunization in BALB/c mice. The immunogenicity, specificity, and ability to induce antibodies against Lpp20 and cytokine secretion were evaluated. After that, CTB-Lpp20 was intragastrically immunized to investigate the prophylactic and therapeutic efficacy in infected mice. RESULTS The results indicated that the epitope vaccine CTB-Lpp20 possessed good immunogenicity and immunoreactivity and could elicit specific high level of antibodies against Lpp20 and the cytokine of IFN-γ and IL-17. Additionally, CTB-Lpp20 significantly decreased H. pylori colonization in H. pylori challenging mice, and the protection was correlated with IgG, IgA, and sIgA antibody and Th1-type cytokines. CONCLUSION This study will be better for understanding the protective immunity of epitope vaccine, and CTB-Lpp20 may be an alternative strategy for combating H. pylori invasion.
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Affiliation(s)
- Yan Li
- School of Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Zhongbiao Chen
- School of Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Jianbin Ye
- School of Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Lijun Ning
- School of Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Jun Luo
- Department of microbiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Lili Zhang
- School of Nursing, Southern Medical University, Guangzhou, 510515, China
| | - Yin Jiang
- School of Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Yue Xi
- School of Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Yunshan Ning
- School of Biotechnology, Southern Medical University, Guangzhou, 510515, China
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20
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Therapeutic efficacy of oral immunization with a non-genetically modified Lactococcus lactis-based vaccine CUE-GEM induces local immunity against Helicobacter pylori infection. Appl Microbiol Biotechnol 2016; 100:6219-6229. [DOI: 10.1007/s00253-016-7333-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Revised: 01/04/2016] [Accepted: 01/17/2016] [Indexed: 12/11/2022]
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21
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Libânio D, Dinis-Ribeiro M, Pimentel-Nunes P. Helicobacter pylori and microRNAs: Relation with innate immunity and progression of preneoplastic conditions. World J Clin Oncol 2015; 6:111-132. [PMID: 26468448 PMCID: PMC4600186 DOI: 10.5306/wjco.v6.i5.111] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 06/22/2015] [Accepted: 08/04/2015] [Indexed: 02/06/2023] Open
Abstract
The accepted paradigm for intestinal-type gastric cancer pathogenesis is a multistep progression from chronic gastritis induced by Helicobacter pylori (H. pylori) to gastric atrophy, intestinal metaplasia, dysplasia and ultimately gastric cancer. The genetic and molecular mechanisms underlying disease progression are still not completely understood as only a fraction of colonized individuals ever develop neoplasia suggesting that bacterial, host and environmental factors are involved. MicroRNAs are noncoding RNAs that may influence H. pylori-related pathology through the regulation of the transcription and expression of various genes, playing an important role in inflammation, cell proliferation, apoptosis and differentiation. Indeed, H. pylori have been shown to modify microRNA expression in the gastric mucosa and microRNAs are involved in the immune host response to the bacteria and in the regulation of the inflammatory response. MicroRNAs have a key role in the regulation of inflammatory pathways and H. pylori may influence inflammation-mediated gastric carcinogenesis possibly through DNA methylation and epigenetic silencing of tumor suppressor microRNAs. Furthermore, microRNAs influenced by H. pylori also have been found to be involved in cell cycle regulation, apoptosis and epithelial-mesenchymal transition. Altogether, microRNAs seem to have an important role in the progression from gastritis to preneoplastic conditions and neoplastic lesions and since each microRNA can control the expression of hundreds to thousands of genes, knowledge of microRNAs target genes and their functions are of paramount importance. In this article we present a comprehensive review about the role of microRNAs in H. pylori gastric carcinogenesis, identifying the microRNAs downregulated and upregulated in the infection and clarifying their biological role in the link between immune host response, inflammation, DNA methylation and gastric carcinogenesis.
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22
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Walduck A, Andersen LP, Raghavan S. Inflammation, Immunity, and Vaccines for Helicobacter pylori Infection. Helicobacter 2015; 20 Suppl 1:17-25. [PMID: 26372820 DOI: 10.1111/hel.12252] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
During the last year, a variety of studies have been published that increases our understanding of the basic mechanisms of immunity and inflammation in Helicobacter pylori infection and progression to gastric cancer. Innate immune regulation and epithelial cell response were covered by several studies that contribute with new insights in the host response to H. pylori infection. Also, the adaptive immune response to H. pylori and particularly the role of IL-22 have been addressed in some studies. These advances may improve vaccine development where new strategies have been published. Two major studies analyzed H. pylori genomes of 39 worldwide strains and looked at the protein profiles. In addition, multi-epitope vaccines for therapeutic use have been investigated. Studies on different adjuvants and delivery systems have also given us new insights. This review presents articles from the last year that reveal detailed insight into immunity and regulation of inflammation, the contribution of immune cells to the development of gastric cancer, and understanding mechanisms of vaccine-induced protection.
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Affiliation(s)
- Anna Walduck
- Health Innovations Research Institute, School of Applied Sciences RMIT University, Bundoora, Melbourne, Vic., Australia
| | - Leif P Andersen
- Department of Infection Control, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Sukanya Raghavan
- Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
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23
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A novel chimeric flagellum fused with the multi-epitope vaccine CTB-UE prevents Helicobacter pylori-induced gastric cancer in a BALB/c mouse model. Appl Microbiol Biotechnol 2015; 99:9495-502. [DOI: 10.1007/s00253-015-6705-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 05/13/2015] [Accepted: 05/17/2015] [Indexed: 12/16/2022]
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24
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Baldauf KJ, Royal JM, Hamorsky KT, Matoba N. Cholera toxin B: one subunit with many pharmaceutical applications. Toxins (Basel) 2015; 7:974-96. [PMID: 25802972 PMCID: PMC4379537 DOI: 10.3390/toxins7030974] [Citation(s) in RCA: 132] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 03/16/2015] [Indexed: 12/22/2022] Open
Abstract
Cholera, a waterborne acute diarrheal disease caused by Vibrio cholerae, remains prevalent in underdeveloped countries and is a serious health threat to those living in unsanitary conditions. The major virulence factor is cholera toxin (CT), which consists of two subunits: the A subunit (CTA) and the B subunit (CTB). CTB is a 55 kD homopentameric, non-toxic protein binding to the GM1 ganglioside on mammalian cells with high affinity. Currently, recombinantly produced CTB is used as a component of an internationally licensed oral cholera vaccine, as the protein induces potent humoral immunity that can neutralize CT in the gut. Additionally, recent studies have revealed that CTB administration leads to the induction of anti-inflammatory mechanisms in vivo. This review will cover the potential of CTB as an immunomodulatory and anti-inflammatory agent. We will also summarize various recombinant expression systems available for recombinant CTB bioproduction.
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Affiliation(s)
- Keegan J Baldauf
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
| | - Joshua M Royal
- Owensboro Cancer Research Program of James Graham Brown Cancer Center at University of Louisville School of Medicine, Owensboro, KY 42303, USA.
| | - Krystal Teasley Hamorsky
- Owensboro Cancer Research Program of James Graham Brown Cancer Center at University of Louisville School of Medicine, Owensboro, KY 42303, USA.
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA.
| | - Nobuyuki Matoba
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
- Owensboro Cancer Research Program of James Graham Brown Cancer Center at University of Louisville School of Medicine, Owensboro, KY 42303, USA.
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