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Shirani M, Shariati S, Bazdar M, Sojoudi Ghamnak F, Moradi M, Shams Khozani R, Taki E, Arabsorkhi Z, Heidary M, Eskandari DB. The immunopathogenesis of Helicobacter pylori-induced gastric cancer: a narrative review. Front Microbiol 2024; 15:1395403. [PMID: 39035439 PMCID: PMC11258019 DOI: 10.3389/fmicb.2024.1395403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 05/06/2024] [Indexed: 07/23/2024] Open
Abstract
Helicobacter pylori infection is a well-established risk factor for the development of gastric cancer (GC). Understanding the immunopathogenesis underlying this association is crucial for developing effective preventive and therapeutic strategies. This narrative review comprehensively explores the immunopathogenesis of H. pylori-induced GC by delving into several key aspects, emphasizing the pivotal roles played by H. pylori virulence factors, including cytotoxin-associated gene A (cagA) and vacuolating cytotoxin A (vacA), blood group antigen-binding adhesin (babA), and sialic acid binding adhesin (sabA). Moreover, the review focuses on the role of toll-like receptors (TLRs) and cytokines in the complex interplay between chronic infection and gastric carcinogenesis. Finally, the study examines the association between H. pylori evasion of the innate and adaptive immune response and development of GC. A comprehensive understanding of the immunopathogenesis of H. pylori-induced GC is essential for designing targeted interventions to prevent and manage this disease. Further research is warranted to elucidate the intricate immune responses involved and identify potential therapeutic targets to improve patient outcomes.
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Affiliation(s)
- Maryam Shirani
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeedeh Shariati
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Monireh Bazdar
- School of Medicine, Razi Hospital, Ilam University of Medical Sciences, Ilam, Iran
| | | | - Melika Moradi
- Department of Microbiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Elahe Taki
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zahra Arabsorkhi
- Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Mohsen Heidary
- Department of Laboratory Sciences, School of Paramedical Sciences, Sabzevar University of Medical Sciences, Sabzevar, Iran
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2
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Zhou J, Zhang M, Wang H, Zhong X, Yang X. Role of Helicobacter pylori virulence factors and alteration of the Tumor Immune Microenvironment: challenges and opportunities for Cancer Immunotherapy. Arch Microbiol 2024; 206:167. [PMID: 38485861 DOI: 10.1007/s00203-024-03908-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/19/2024] [Accepted: 02/22/2024] [Indexed: 03/19/2024]
Abstract
Various forms of malignancies have been linked to Helicobacter pylori. Despite advancements in chemotherapeutic and surgical approaches, the management of cancer, particularly at advanced stages, increasingly relies on the integration of immunotherapy. As a novel, safe therapeutic modality, immunotherapy harnesses the immune system of the patient to treat cancer, thereby broadening treatment options. However, there is evidence that H. pylori infection may influence the effectiveness of immunotherapy in various types of cancer. This association is related to H. pylori virulence factors and the tumor microenvironment. This review discusses the influence of H. pylori infection on immunotherapy in non-gastrointestinal and gastrointestinal tumors, the mechanisms underlying this relationship, and directions for the development of improved immunotherapy strategies.
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Affiliation(s)
- Junyi Zhou
- Department of Oncology, The Huai'an Clinical College of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Minna Zhang
- Department of Gastroenterology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - HongGang Wang
- Department of Gastroenterology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Xiaomin Zhong
- Department of Oncology, The Huai'an Clinical College of Xuzhou Medical University, Huai'an, Jiangsu, China.
| | - XiaoZhong Yang
- Department of Gastroenterology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China.
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3
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Grzywa R, Łupicka-Słowik A, Sieńczyk M. IgYs: on her majesty's secret service. Front Immunol 2023; 14:1199427. [PMID: 37377972 PMCID: PMC10291628 DOI: 10.3389/fimmu.2023.1199427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 05/16/2023] [Indexed: 06/29/2023] Open
Abstract
There has been an increasing interest in using Immunoglobulin Y (IgY) antibodies as an alternative to "classical" antimicrobials. Unlike traditional antibiotics, they can be utilized on a continual basis without leading to the development of resistance. The veterinary IgY antibody market is growing because of the demand for minimal antibiotic use in animal production. IgY antibodies are not as strong as antibiotics for treating infections, but they work well as preventative agents and are natural, nontoxic, and easy to produce. They can be administered orally and are well tolerated, even by young animals. Unlike antibiotics, oral IgY supplements support the microbiome that plays a vital role in maintaining overall health, including immune system function. IgY formulations can be delivered as egg yolk powder and do not require extensive purification. Lipids in IgY supplements improve antibody stability in the digestive tract. Given this, using IgY antibodies as an alternative to antimicrobials has garnered interest. In this review, we will examine their antibacterial potential.
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de Brito BB, Lemos FFB, Carneiro CDM, Viana AS, Barreto NMPV, Assis GADS, Braga BDC, Santos MLC, Silva FAFD, Marques HS, Silva NOE, de Melo FF. Immune response to Helicobacter pylori infection and gastric cancer development. World J Meta-Anal 2021; 9:257-276. [DOI: 10.13105/wjma.v9.i3.257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/24/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
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5
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Padda J, Khalid K, Cooper AC, Jean-Charles G. Association Between Helicobacter pylori and Gastric Carcinoma. Cureus 2021; 13:e15165. [PMID: 34168929 PMCID: PMC8216031 DOI: 10.7759/cureus.15165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric carcinoma is the third leading cause of cancer mortality worldwide. In 2018, the incidence of gastric carcinoma worldwide was over 1,000,000 new cases, with approximately 783,000 deaths. The rate of new cases is noticeably increased in Eastern Asia. Helicobacter pylori is responsible for the increased incidence of gastric cancer. In the year 2015, H. pylori had an approximate prevalence of 4.4 billion positive cases worldwide, with the most positive cases found within the region of Africa, Latin America and the Caribbean, and of Asia. H. pylori is known to have multiple strains which allow it to survive in the host cell epithelium chronically. Research has shown many factors which play a significant role in developing infection and thereafter its progression to gastric carcinoma. After H. pylori colonizes the gastric mucosa, its effects can be potentiated by virulence factors, host factors, and environmental factors. H. pylori contains virulence factors that aid in the adhesion, translocation, inflammation, and infectivity of the host gastric epithelium. It alters the functions of the host immune response and cytokines, utilizing these factors to invade and persist in the gastric epithelium for a long period of time. The human body will identify H. pylori to be foreign and will exacerbate an inflammatory response in an effort to eradicate the bacterium. Consequently, this will cause H. pylori to induce a serious infection which may progress to cancer. In this review, we will discuss the various factors involved in the infectious process of H. pylori and how they help the infection progress to gastric carcinoma. This will allow us to better understand and modulate treatments to effectively eradicate this bacterium before it triggers the body into developing cancer.
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Affiliation(s)
| | | | | | - Gutteridge Jean-Charles
- Internal Medicine, Advent Health and Orlando Health Hospital/JC Medical Center, Orlando, USA
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6
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Baj J, Forma A, Sitarz M, Portincasa P, Garruti G, Krasowska D, Maciejewski R. Helicobacter pylori Virulence Factors-Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment. Cells 2020; 10:27. [PMID: 33375694 PMCID: PMC7824444 DOI: 10.3390/cells10010027] [Citation(s) in RCA: 198] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer constitutes one of the most prevalent malignancies in both sexes; it is currently the fourth major cause of cancer-related deaths worldwide. The pathogenesis of gastric cancer is associated with the interaction between genetic and environmental factors, among which infection by Helicobacter pylori (H. pylori) is of major importance. The invasion, survival, colonization, and stimulation of further inflammation within the gastric mucosa are possible due to several evasive mechanisms induced by the virulence factors that are expressed by the bacterium. The knowledge concerning the mechanisms of H. pylori pathogenicity is crucial to ameliorate eradication strategies preventing the possible induction of carcinogenesis. This review highlights the current state of knowledge and the most recent findings regarding H. pylori virulence factors and their relationship with gastric premalignant lesions and further carcinogenesis.
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Affiliation(s)
- Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-400 Lublin, Poland;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Monika Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Danuta Krasowska
- Department of Dermatology, Venerology and Paediatric Dermatology of Medical University of Lublin, 20-081 Lublin, Poland;
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Zhao H, Xu L, Xu Z, Ding Y, Yu H, Zhang Y, Wu Y, Li B, Ji X. Investigation on the role of gene hp0788 in Helicobacter pylori in infecting gastric epithelial cells. Microb Pathog 2019; 137:103739. [PMID: 31513896 DOI: 10.1016/j.micpath.2019.103739] [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: 04/09/2019] [Revised: 08/20/2019] [Accepted: 09/08/2019] [Indexed: 11/30/2022]
Abstract
Helicobacter pylori infection can cause a wide range of digestive diseases. Gene hp0788 encodes an outer membrane protein HofF, which can reduce the bacterial adherence to the GES-1 cells and affect pathogenesis of H. pylori. In this study, the role of hp0788 in H. pylori infection was further analyzed. RNA-seq data showed that two genes (hp0523 and hp0539), located on the cagPAI, were down-regulated in Δ0788 mutant. The changes were confirmed through qRT-PCR, and the expression of these two genes will be almost recovered to the normal level in complemented strain. These two genes, hp0523 and hp0539, are known to be necessary for integrated T4SS, which related to CagA translocation and IL-8 induction. In H. pylori infected assay, lower amount of phosphorylated CagA and lower induction of IL-8 were both detected in GES-1 cells infected by Δ0788 mutant, compared with the wild type strain. Meanwhile, these reductions almost recovered to the wild-type level in complemented strain. These results reveal that there is a correlation between hp0788 disruption and CagA/IL-8 decline. Deletion of CagA-encoding gene (hp0547) in Δ0788 mutant was further constructed. The double deleted mutant shows lower IL-8-inducing capability than Δ0788 mutant, indicated the correlation between deficiency of CagA and reduced IL-8 production. These results together imply that disruption of hp0788 might affect the efficiency of T4SS and CagA injection, then weaken the induction of IL-8 in infected GES-1 cells.
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Affiliation(s)
- Huilin Zhao
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China
| | - Linlin Xu
- Department of Neurology, Second Hospital, Shandong University, Jinan, China
| | - Zheng Xu
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China
| | - Yunfei Ding
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China
| | - Haonan Yu
- School of Clinical Medicine, Binzhou Medical University, Yantai, China
| | - Ying Zhang
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China
| | - Yulong Wu
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China
| | - Boqing Li
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China.
| | - Xiaofei Ji
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China.
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8
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Yadegar A, Mohabati Mobarez A, Zali MR. Genetic diversity and amino acid sequence polymorphism in Helicobacter pylori CagL hypervariable motif and its association with virulence markers and gastroduodenal diseases. Cancer Med 2019; 8:1619-1632. [PMID: 30873747 PMCID: PMC6488209 DOI: 10.1002/cam4.1941] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 11/22/2018] [Accepted: 12/03/2018] [Indexed: 12/19/2022] Open
Abstract
Genetic variability in cagL gene especially within the Helicobacter pylori CagL hypervariable motif (CagLHM) may affect the development of gastric cancer. Therefore, this study was conducted to investigate the association of CagL diversity with clinical outcomes and with H pylori virulence markers. A total of 126 patients with different gastric diseases including non-ulcer dyspepsia (NUD), peptic ulcer disease (PUD), gastric erosion (GE), and gastric cancer (GC) were enrolled. H pylori was cultured from gastric biopsies, and the isolates were screened for the presence of cagL, cagA, vacA, babA2, sabA, and cagPAI integrity by PCR. The amino acid polymorphisms of cagL were analyzed using DNA sequencing. We isolated 61 (48.4%) H pylori strains from 36 NUD, eight PUD, 12 GE, and five GC patients. Almost all isolates were cagL positive (97%), and their RGD, RHS, and SKIIVK motifs were highly conserved. Among 10 CagLHM variants identified, NEIGQ and NKIGQ were detected as the most prevalent sequences. Interestingly, a significant association was found between the presence of NKMGK and PUD (P = 0.002). Notably, the NEIGQ isolates with multiple C-type EPIYA repeat that carried intact cagPAI correlated with disease risk for PUD, GE, and GC (P = 0.021). In conclusion, we identified novel variants of H pylori CagLHM sequences in Iranian population such as NKMGK, which was associated with disease risk for PUD. Further studies using a large number of strains are required to better clarify the function of certain CagLHM motifs in gastric carcinogenesis and disease outcome.
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Affiliation(s)
- Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | | | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
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Beckett AC, Loh JT, Chopra A, Leary S, Lin AS, McDonnell WJ, Dixon BREA, Noto JM, Israel DA, Peek RM, Mallal S, Algood HMS, Cover TL. Helicobacter pylori genetic diversification in the Mongolian gerbil model. PeerJ 2018; 6:e4803. [PMID: 29796347 PMCID: PMC5961626 DOI: 10.7717/peerj.4803] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 04/30/2018] [Indexed: 12/12/2022] Open
Abstract
Helicobacter pylori requires genetic agility to infect new hosts and establish long-term colonization of changing gastric environments. In this study, we analyzed H. pylori genetic adaptation in the Mongolian gerbil model. This model is of particular interest because H. pylori-infected gerbils develop a high level of gastric inflammation and often develop gastric adenocarcinoma or gastric ulceration. We analyzed the whole genome sequences of H. pylori strains cultured from experimentally infected gerbils, in comparison to the genome sequence of the input strain. The mean annualized single nucleotide polymorphism (SNP) rate per site was 1.5e−5, which is similar to the rates detected previously in H. pylori-infected humans. Many of the mutations occurred within or upstream of genes associated with iron-related functions (fur, tonB1, fecA2, fecA3, and frpB3) or encoding outer membrane proteins (alpA, oipA, fecA2, fecA3, frpB3 and cagY). Most of the SNPs within coding regions (86%) were non-synonymous mutations. Several deletion or insertion mutations led to disruption of open reading frames, suggesting that the corresponding gene products are not required or are deleterious during chronic H. pylori colonization of the gerbil stomach. Five variants (three SNPs and two deletions) were detected in isolates from multiple animals, which suggests that these mutations conferred a selective advantage. One of the mutations (FurR88H) detected in isolates from multiple animals was previously shown to confer increased resistance to oxidative stress, and we now show that this SNP also confers a survival advantage when H. pylori is co-cultured with neutrophils. Collectively, these analyses allow the identification of mutations that are positively selected during H. pylori colonization of the gerbil model.
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Affiliation(s)
- Amber C Beckett
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - John T Loh
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Abha Chopra
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia
| | - Shay Leary
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia
| | - Aung Soe Lin
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Wyatt J McDonnell
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Beverly R E A Dixon
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Jennifer M Noto
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Dawn A Israel
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Richard M Peek
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.,Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Simon Mallal
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.,Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America.,Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia
| | - Holly M Scott Algood
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America.,Tennessee Valley Healthcare System, Veterans Affairs, Nashville, TN, United States of America
| | - Timothy L Cover
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.,Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America.,Tennessee Valley Healthcare System, Veterans Affairs, Nashville, TN, United States of America
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10
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Horridge DN, Begley AA, Kim J, Aravindan N, Fan K, Forsyth MH. Outer inflammatory protein a (OipA) of Helicobacter pylori is regulated by host cell contact and mediates CagA translocation and interleukin-8 response only in the presence of a functional cag pathogenicity island type IV secretion system. Pathog Dis 2017; 75:4494363. [PMID: 29040466 PMCID: PMC6433299 DOI: 10.1093/femspd/ftx113] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 10/11/2017] [Indexed: 12/11/2022] Open
Abstract
OipA is a phase-variable virulence factor of Helicobacter pylori. Mutations in oipA to turn the gene phase on in a cag pathogenicity island (PAI)-negative strain of H. pylori (J68) or phase off in a cag PAI-positive strain (26695) demonstrated that phase on oipA alleles in both strains had both increased oipA mRNA and human gastric adenocarcinoma (AGS) cell adherence compared to isogenic oipA phase off mutants. An oipA phase off mutant of H. pylori 26695 demonstrated decreased IL-8 secretion by AGS cells and failure to translocate the cag PAI effector CagA. Increased attachment by OipA expressing cag PAI-negative H. pylori J68 failed to alter secreted IL-8 levels. Thus, OipA is necessary but not sufficient for the induction of IL-8; however, it is necessary for translocation of the oncoprotein CagA. Perhaps the nearly invariant phase on status of oipA alleles among cag PAI-positive H. pylori isolates relates to the role of this outer membrane protein in effective translocation of CagA. oipA mRNA comparisons between AGS cell-adherent and non-adherent H. pylori 26695 revealed significantly greater levels in the adherent cells. This may allow H. pylori to adapt to conditions of host cell contact by altering expression of this virulence factor.
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Affiliation(s)
- Danielle N Horridge
- Department of Biology, The College of William and Mary, Williamsburg VA 23187, USA
| | - Allison A Begley
- Department of Biology, The College of William and Mary, Williamsburg VA 23187, USA
- The Governor's School of Science and Technology. Hampton, VA 23666, USA
| | - June Kim
- Department of Biology, The College of William and Mary, Williamsburg VA 23187, USA
| | - Neeraja Aravindan
- Department of Biology, The College of William and Mary, Williamsburg VA 23187, USA
| | - Kexin Fan
- Department of Biology, The College of William and Mary, Williamsburg VA 23187, USA
| | - Mark H Forsyth
- Department of Biology, The College of William and Mary, Williamsburg VA 23187, USA
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Ji X, Wang Y, Li J, Rong Q, Chen X, Zhang Y, Liu X, Li B, Zhao H. Application of FLP-FRT System to Construct Unmarked Deletion in Helicobacter pylori and Functional Study of Gene hp0788 in Pathogenesis. Front Microbiol 2017; 8:2357. [PMID: 29238332 PMCID: PMC5712585 DOI: 10.3389/fmicb.2017.02357] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 11/15/2017] [Indexed: 12/21/2022] Open
Abstract
Helicobacter pylori is a Gram-negative, microaerophilic bacterium associated with human gastric diseases. Further investigations on virulence genes are still required to clarify the pathogenic mechanism of H. pylori and the heterogeneous problem of infection. In order to develop an efficient and accurate method to study gene functions in H. pylori pathogenesis, an unmarked deletion method for both a single gene and a large fragment was established based on the FLP-FRT recombination system. Using this method, the gene hp0788, encoding an outer membrane protein (HofF), was deleted. Deletion of hp0788 did not affect growth or motility of H. pylori, but reduced the adherence of the bacteria to gastric epithelial cells. The apoptosis of GES-1 cells caused by H. pylori infection was also reduced by the defection of hp0788. These suggest that hp0788 takes part in the bacterium-host interaction and plays an important role in H. pylori infection. Furthermore, a large genomic fragment deletion from hp0541 to hp0547 in cag pathogenicity island was also successfully achieved using FLP-FRT method. The innovative application of the FLP-FRT recombination system in H. pylori to construct unmarked deletion would provide a helpful tool for further function research of putative pathogenic genes and contribute to the understanding of H. pylori pathogenesis.
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Affiliation(s)
- Xiaofei Ji
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China
| | - Ying Wang
- Central Laboratory, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China
| | - Jiaojiao Li
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China
| | - Qianyu Rong
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China
| | - Xingxing Chen
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China
| | - Ying Zhang
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China
| | - Xiaoning Liu
- Central Laboratory, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China
| | - Boqing Li
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China
| | - Huilin Zhao
- Department of Pathogenic Biology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, China
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12
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Yakoob J, Abbas Z, Mehmood MH, Tariq K, Saleem SA, Awan S, Malik A, Hamid S, Khan R, Jafri W. Helicobacter pylori outer membrane protein Q genotypes and their susceptibility to anti-adhesive phytotherapeutic agents. JOURNAL OF INTEGRATIVE MEDICINE 2017; 15:398-406. [PMID: 28844217 DOI: 10.1016/s2095-4964(17)60359-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Helicobacter pylori is a Gram-negative organism. Its outer membrane protein Q (HopQ) mediates host-pathogen interactions; HopQ genotypes 1 and 2 are found associating with gastroduodenal pathologies. The authors measured the anti-adhesion effects of the extracts of Abelmoschus esculentus, Zingiber officinale, Trachyspermum ammi, Glycyrrhiza glabra, Curcuma longa and Capsicum annum against HopQ genotypes and H. pylori cytotoxin-associated gene A (CagA). METHODS DNA was extracted by polymerase chain reaction of the HopQ genotypes (i.e., type 1, type 2 and CagA) from 115 H. pylori strains. The effect of the extracts from selected dietary ingredients was determined using a gastric adenocarcinoma cell line and a quantitative DNA fragmentation assay. The anti-adhesive effect of these extracts on H. pylori was tested using an anti-adhesion analysis. RESULTS C. annum, C. longa and A. esculentus showed prominent anti-adhesion effects with resultant values of 17.3% ± 2.9%, 14.6% ± 3.7%, 13.8% ± 3.6%, respectively, against HopQ type 1 and 13.1% ± 1.7%, 12.1% ± 2%, 11.1% ± 1.6%, respectively, against HopQ type 2. C. longa (93%), C. annum (89%) and A. esculentus (75%) had better anti-adhesive activity against H. pylori with HopQ type 1 compared to HopQ type 2 with respective values of 70%, 64% and 51%. Extracts of C. annum (14.7% ± 4.1%), A. esculentus (12.3% ± 4.1%) and Z. officinale (8.4% ± 2.8%) had an anti-adhesion effect against CagA-positive H. pylori strains compared to CagA-negative strains. CONCLUSION The anti-adhesion properties of the tested phytotherapeutic dietary ingredients were varied with HopQ genotypes. HopQ type 1 was found to be more sensitive to extracts of C. annum, C. longa and A. esculentus compared to the HopQ type 2 genotype.
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Affiliation(s)
- Javed Yakoob
- Department of Medicine, Aga Khan University, Karachi 74800, Pakistan
- Department of Biological Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan
| | - Zaigham Abbas
- Department of Medicine, Aga Khan University, Karachi 74800, Pakistan
| | - Malik Hassan Mehmood
- Department of Biological Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan
| | - Kanwal Tariq
- Department of Medicine, Aga Khan University, Karachi 74800, Pakistan
| | | | - Safia Awan
- Department of Medicine, Aga Khan University, Karachi 74800, Pakistan
| | - Abdul Malik
- Department of Biological Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan
| | - Saeed Hamid
- Department of Medicine, Aga Khan University, Karachi 74800, Pakistan
| | - Rustam Khan
- Department of Medicine, Aga Khan University, Karachi 74800, Pakistan
| | - Wasim Jafri
- Department of Medicine, Aga Khan University, Karachi 74800, Pakistan
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Sohrabi M, Khashei R, Alizadeh M, Asl MKH, Nejati MA, Dara M, Bazargani A. Low Rate of babA2 Genotype among Iranian Helicobacter pylori Clinical Isolates. J Clin Diagn Res 2017; 11:DC32-DC36. [PMID: 28892894 DOI: 10.7860/jcdr/2017/24810.10277] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 05/04/2017] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The Blood Group Antigen-Binding Adhesion (babA), Outer Inflammatory Protein (oipA) and Sialic Acid-Binding Adhesin (sabA) as outer membrane proteins involved in Helicobacter pylori adherence to gastric mucosa have been suggested to have a role in the pathogenesis. AIM To investigate the frequency of H. pylori isolates babA2, oipA and sabA genes in Iranian dyspeptic patients. MATERIALS AND METHODS DNAs were extracted from H. pylori -positive cultures taken from 100 different dyspeptic patients. Genotyping was performed by Polymerase Chain Reaction (PCR), using the specific primers for babA2, oipA and sabA genes. Chi square test was used to investigate association between variables, p<0.05 was considered statistically significant. RESULTS All (100%) isolates possessed oipA and sabA genotypes, whereas babA2 was detected in 22% of isolates. There was no significant relationship between presence of genes with clinical outcome. The combined genotype oipA +/sabA +/ babA2- was correlated with gastritis. The rate of babA2 genotype in our isolates was lower than other Iranian reports. CONCLUSION Frequency of babA2 genotype among H. pylori isolates from Southwest of Iran is considerably less than other regions of Iran. Due to heterogeneity of H. pylori strains in different geographic regions, further work will be needed to understand the role of these virulence genes in H. pylori pathogenesis and their possible association with disease outcome.
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Affiliation(s)
- Maryam Sohrabi
- Student, Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Khashei
- Assistant Professor, Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahvash Alizadeh
- Assistant Professor, Department of Internal Medicine, Gastroenterology Ward, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad-Kazem Hosseini Asl
- Associate Professor, Department of Internal Medicine, Gastroenterology Ward, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad-Ali Nejati
- Assistant Professor, Department of Internal Medicine, Gastroenterology Ward, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahintaj Dara
- Ph.D Student, Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdollah Bazargani
- Associate Professor, Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Ansari S, Yamaoka Y. Helicobacter pylori BabA in adaptation for gastric colonization. World J Gastroenterol 2017; 23:4158-4169. [PMID: 28694656 PMCID: PMC5483490 DOI: 10.3748/wjg.v23.i23.4158] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/12/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) as a causative agent of gastric complications, is well adapted for the colonization of gastric mucosa. Although the infectious process depends on several factors, the adhesion to the gastric mucosa is the first and important step. Among several outer membrane proteins, BabA is one of the significant protein involving in many inflammatory processes in addition to its role in the attachment for the persistent colonization. We performed a PubMed search using the key words: “babA”, “pylori”, “gastric complications”, “homologous recombination”, “slipped strand mispairing”; a total of 249 articles were displayed. Of these we mainly focused on articles with the full text in English and published between 2005 and 2016. H. pylori BabA is involved in binding with receptors; however, its synthesis is regulated by phase variation. In this review we confirm that H. pylori babA can be modulated at the molecular and functional levels to adapt to the stress within the gastro-intestinal tract.
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Gu H. Role of Flagella in the Pathogenesis of Helicobacter pylori. Curr Microbiol 2017; 74:863-869. [PMID: 28444418 PMCID: PMC5447363 DOI: 10.1007/s00284-017-1256-4] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 04/18/2017] [Indexed: 12/15/2022]
Abstract
This review aimed to investigate the role of Helicobacter pylori flagella on the pathogenicity of this bacterium in humans. Helicobacter pylori is a flagellated pathogen that colonizes the human gastroduodenal mucosa and produces inflammation, and is responsible for gastrointestinal disease. Its pathogenesis is attributed to colonization and virulence factors. The primary function of H. pylori flagella is to provide motility. We believe that H. pylori flagella play an important role in the colonization of the gastrointestinal mucosa. Therefore, we reviewed previous studies on flagellar morphology and motility in order to explore the relationship between H. pylori flagella and pathogenicity. Further investigation is required to confirm the association between flagella and pathogenicity in H. pylori.
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Affiliation(s)
- Haiying Gu
- Medical School, Ningbo University, Ningbo, 315211, China.
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16
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Functional study of gene hp0169 in Helicobacter pylori pathogenesis. Microb Pathog 2017; 104:225-231. [PMID: 28131950 DOI: 10.1016/j.micpath.2017.01.039] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 01/17/2017] [Accepted: 01/24/2017] [Indexed: 12/15/2022]
Abstract
Many virulence genes have been reported to play important roles in Helicobacter pylori pathogenesis. However the detailed mechanisms of many of them have not been completely clear. In this study, we found gene hp0169, encoding a putative collagenase (HpPrtC), was involved in pathogenesis of H. pylori. Recombinant HpPrtC shows activities to both native and heat-denatured collagens. This result indicated that HpPrtC may act as a virulence factor to help the bacterium colonize in their host stomach by degrading surrounding collagens. hp0169 was deleted by homologous recombination to study its function in bacterium-host cell interaction. For the pathogenic functions on the host cells, the hp0169 mutant exhibits no significant changes on inducing apoptosis of GES-1 cells. However, the viability and proliferation rate of GES-1 cells infected with mutant strain were higher than the cells infected with wild-type strain. These results indicated that except for its collagenolytic activity, HpPrtC might participate in H. pylori pathogenesis through an additional pathway. Functional studies on hp0169 involved in pathogenesis would shed light on deep understanding of the pathogenic mechanism of H. pylori.
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Su YL, Huang HL, Huang BS, Chen PC, Chen CS, Wang HL, Lin PH, Chieh MS, Wu JJ, Yang JC, Chow LP. Combination of OipA, BabA, and SabA as candidate biomarkers for predicting Helicobacter pylori-related gastric cancer. Sci Rep 2016; 6:36442. [PMID: 27819260 PMCID: PMC5098209 DOI: 10.1038/srep36442] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 10/17/2016] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori ) infection is a major cause of chronic gastritis and is highly related to duodenal ulcer (DU) and gastric cancer (GC). To identify H. pylori-related GC biomarkers with high seropositivity in GC patients, differences in levels of protein expression between H. pylori from GC and DU patients were analyzed by isobaric tag for relative and absolute quantitation (iTRAQ). In total, 99 proteins showed increased expression (>1.5-fold) in GC patients compared to DU patients, and 40 of these proteins were categorized by KEGG pathway. The four human disease-related adhesin identified, AlpA, OipA, BabA, and SabA, were potential GC-related antigens, with a higher seropositivity in GC patients (n = 76) than in non-GC patients (n = 100). Discrimination between GC and non-GC patients was improved using multiple antigens, with an odds ratio of 9.16 (95% CI, 2.99-28.07; p < 0.0001) for three antigens recognized. The optimized combination of OipA, BabA, and SabA gave a 77.3% correct prediction rate. A GC-related protein microarray was further developed using these antigens. The combination of OipA, BabA, and SabA showed significant improvement in the diagnostic accuracy and the protein microarray containing above antigens should provide a rapid and convenient diagnosis of H. pylori-associated GC.
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Affiliation(s)
- Yu-Lin Su
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsiang-Ling Huang
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Bo-Shih Huang
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Po-Chung Chen
- Graduate Institute of Systems Biology and Bioinformatics, National Central University, Taoyuan, Taiwan
| | - Chien-Sheng Chen
- Graduate Institute of Systems Biology and Bioinformatics, National Central University, Taoyuan, Taiwan
| | - Hong-Long Wang
- Department of Statistics, National Taipei University, New Taipei City, Taiwan
| | - Pin-Hsin Lin
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Meng-Shu Chieh
- First Core Laboratory, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jiunn-Jong Wu
- Department of Medical Laboratory Science and Biotechnology, Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jyh-Chin Yang
- Department of Internal Medicine, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Lu-Ping Chow
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan
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Ji X, Zhao H, Zhang Y, Chen X, Li J, Li B. Construction of Novel Plasmid Vectors for Gene Knockout in Helicobacter pylori. Curr Microbiol 2016; 73:897-903. [DOI: 10.1007/s00284-016-1140-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 09/13/2016] [Indexed: 02/07/2023]
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Helicobacter pylori CagA Suppresses Apoptosis through Activation of AKT in a Nontransformed Epithelial Cell Model of Glandular Acini Formation. BIOMED RESEARCH INTERNATIONAL 2015; 2015:761501. [PMID: 26557697 PMCID: PMC4628739 DOI: 10.1155/2015/761501] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 04/16/2015] [Accepted: 04/20/2015] [Indexed: 02/07/2023]
Abstract
H. pylori infection is the most important environmental risk to develop gastric cancer, mainly through its virulence factor CagA. In vitro models of CagA function have demonstrated a phosphoprotein activity targeting multiple cellular signaling pathways, while cagA transgenic mice develop carcinomas of the gastrointestinal tract, supporting oncogenic functions. However, it is still not completely clear how CagA alters cellular processes associated with carcinogenic events. In this study, we evaluated the capacity of H. pylori CagA positive and negative strains to alter nontransformed MCF-10A glandular acini formation. We found that CagA positive strains inhibited lumen formation arguing for an evasion of apoptosis activity of central acini cells. In agreement, CagA positive strains induced a cell survival activity that correlated with phosphorylation of AKT and of proapoptotic proteins BIM and BAD. Anoikis is a specific type of apoptosis characterized by AKT and BIM activation and it is the mechanism responsible for lumen formation of MCF-10A acini in vitro and mammary glands in vivo. Anoikis resistance is also a common mechanism of invading tumor cells. Our data support that CagA positive strains signaling function targets the AKT and BIM signaling pathway and this could contribute to its oncogenic activity through anoikis evasion.
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Li N, She FF, Lin X. Application of recombinant Helicobacter pylori outer inflammatory protein A peptide for diagnosis of high virulent Helicobacter pylori infection. Shijie Huaren Xiaohua Zazhi 2015; 23:2549-2554. [DOI: 10.11569/wcjd.v23.i16.2549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the feasibility of recombinant Helicobacter pylori (H. pylori) outer inflammatory protein A (OipA) peptide as a clinical diagnostic agent for high virulent H. pylori infection.
METHODS: Serum and gastric mucosa biopsy specimens were obtained from 285 patients who underwent gastroscopy. H. pylori strains were isolated from urease positive samples and some urease negative samples. Isolated strains were identified by microscopy, urease test and 16S rRNA PCR. OipA and cytotoxin-associated gene A (cagA) of the isolates were obtained by PCR and the oipA signal region was analyed after sequencing. OipA antibody in serum specimen was detected using purified recombinant OipA6 peptide, and CagA antibody was detected by indirect ELISA using a commercial kit. The results of oipA gene and OipA antibody as well as OipA antibody and CagA antibody were compared. The feasibility of OipA6 as a diagnostic agent for high virulent H. pylori infection was evaluated.
RESULTS: A total of 83 isolated H. pylori were obtained, of which 66 was positive for oipA signal region (signal region was on in 62, and undefined in 4), and 59 was positive for cagA. The sensitivity, specificity and consistency rate of recombination antigen OipA6 were 95.16%, 95.83% and 95.28%, respectively, which were all higher than those of CagA (77.97%, 87.50% and 80.72%).
CONCLUSION: Recombinant OipA peptide may be used as an antigen for detection of high virulent H. pylori infection.
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