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Clyne M, Ó Cróinín T. Pathogenicity and virulence of Helicobacter pylori: A paradigm of chronic infection. Virulence 2025; 16:2438735. [PMID: 39725863 DOI: 10.1080/21505594.2024.2438735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 11/18/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024] Open
Abstract
Infection with Helicobacter pylori is one of the most common infections of mankind. Infection typically occurs in childhood and persists for the lifetime of the host unless eradicated with antimicrobials. The organism colonizes the stomach and causes gastritis. Most infected individuals are asymptomatic, but infection also causes gastric and duodenal ulceration, and gastric cancer. H. pylori possesses an arsenal of virulence factors, including a potent urease enzyme for protection from acid, flagella that mediate motility, an abundance of outer membrane proteins that can mediate attachment, several immunomodulatory proteins, and an ability to adapt to specific conditions in individual human stomachs. The presence of a type 4 secretion system that injects effector molecules into gastric cells and subverts host cell signalling is associated with virulence. In this review we discuss the interplay of H. pylori colonization and virulence factors with host and environmental factors to determine disease outcome in infected individuals.
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Affiliation(s)
- Marguerite Clyne
- School of Medicine, University College Dublin, Dublin, Ireland
- The Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Tadhg Ó Cróinín
- The Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
- School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
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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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Sedarat Z, Taylor-Robinson AW. Helicobacter pylori Outer Membrane Proteins and Virulence Factors: Potential Targets for Novel Therapies and Vaccines. Pathogens 2024; 13:392. [PMID: 38787244 PMCID: PMC11124246 DOI: 10.3390/pathogens13050392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 04/12/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Helicobacter pylori is a gastric oncopathogen that infects over half of the world's human population. It is a Gram-negative, microaerophilic, helix-shaped bacterium that is equipped with flagella, which provide high motility. Colonization of the stomach is asymptomatic in up to 90% of people but is a recognized risk factor for developing various gastric disorders such as gastric ulcers, gastric cancer and gastritis. Invasion of the human stomach occurs via numerous virulence factors such as CagA and VacA. Similarly, outer membrane proteins (OMPs) play an important role in H. pylori pathogenicity as a means to adapt to the epithelial environment and thereby facilitate infection. While some OMPs are porins, others are adhesins. The epithelial cell receptors SabA, BabA, AlpA, OipA, HopQ and HopZ have been extensively researched to evaluate their epidemiology, structure, role and genes. Moreover, numerous studies have been performed to seek to understand the complex relationship between these factors and gastric diseases. Associations exist between different H. pylori virulence factors, the co-expression of which appears to boost the pathogenicity of the bacterium. Improved knowledge of OMPs is a major step towards combatting this global disease. Here, we provide a current overview of different H. pylori OMPs and discuss their pathogenicity, epidemiology and correlation with various gastric diseases.
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Affiliation(s)
- Zahra Sedarat
- Cellular & Molecular Research Centre, Shahrekord University of Medical Sciences, Shahrekord 8813833435, Iran;
| | - Andrew W. Taylor-Robinson
- College of Health Sciences, VinUniversity, Gia Lam District, Hanoi 67000, Vietnam
- Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 1904, USA
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Bhattacharjee A, Sahoo OS, Sarkar A, Bhattacharya S, Chowdhury R, Kar S, Mukherjee O. Infiltration to infection: key virulence players of Helicobacter pylori pathogenicity. Infection 2024; 52:345-384. [PMID: 38270780 DOI: 10.1007/s15010-023-02159-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 12/13/2023] [Indexed: 01/26/2024]
Abstract
PURPOSE This study aims to comprehensively review the multifaceted factors underlying the successful colonization and infection process of Helicobacter pylori (H. pylori), a prominent Gram-negative pathogen in humans. The focus is on elucidating the functions, mechanisms, genetic regulation, and potential cross-interactions of these elements. METHODS Employing a literature review approach, this study examines the intricate interactions between H. pylori and its host. It delves into virulence factors like VacA, CagA, DupA, Urease, along with phase variable genes, such as babA, babC, hopZ, etc., giving insights about the bacterial perspective of the infection The association of these factors with the infection has also been added in the form of statistical data via Funnel and Forest plots, citing the potential of the virulence and also adding an aspect of geographical biasness to the virulence factors. The biochemical characteristics and clinical relevance of these factors and their effects on host cells are individually examined, both comprehensively and statistically. RESULTS H. pylori is a Gram-negative, spiral bacterium that successfully colonises the stomach of more than half of the world's population, causing peptic ulcers, gastric cancer, MALT lymphoma, and other gastro-duodenal disorders. The clinical outcomes of H. pylori infection are influenced by a complex interplay between virulence factors and phase variable genes produced by the infecting strain and the host genetic background. A meta-analysis of the prevalence of all the major virulence factors has also been appended. CONCLUSION This study illuminates the diverse elements contributing to H. pylori's colonization and infection. The interplay between virulence factors, phase variable genes, and host genetics determines the outcome of the infection. Despite biochemical insights into many factors, their comprehensive regulation remains an understudied area. By offering a panoramic view of these factors and their functions, this study enhances understanding of the bacterium's perspective, i.e. H. pylori's journey from infiltration to successful establishment within the host's stomach.
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Affiliation(s)
- Arghyadeep Bhattacharjee
- Department of Biotechnology, National Institute of Technology Durgapur, Durgapur, West Bengal, 713209, India
- Department of Microbiology, Kingston College of Science, Beruanpukuria, Barasat, West Bengal, 700219, India
| | - Om Saswat Sahoo
- Department of Biotechnology, National Institute of Technology Durgapur, Durgapur, West Bengal, 713209, India
| | - Ahana Sarkar
- Department of Biotechnology, National Institute of Technology Durgapur, Durgapur, West Bengal, 713209, India
| | - Saurabh Bhattacharya
- Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, The Hebrew University of Jerusalem, P.O.B. 12272, 9112001, Jerusalem, Israel
| | - Rukhsana Chowdhury
- School of Biological Sciences, RKM Vivekananda Educational and Research Institute Narendrapur, Kolkata, India
| | - Samarjit Kar
- Department of Mathematics, National Institute of Technology Durgapur, Durgapur, West Bengal, 713209, India
| | - Oindrilla Mukherjee
- Department of Biotechnology, National Institute of Technology Durgapur, Durgapur, West Bengal, 713209, India.
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Jarzab M, Skorko-Glonek J. There Are No Insurmountable Barriers: Passage of the Helicobacter pylori VacA Toxin from Bacterial Cytoplasm to Eukaryotic Cell Organelle. MEMBRANES 2023; 14:11. [PMID: 38248700 PMCID: PMC10821523 DOI: 10.3390/membranes14010011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/20/2023] [Accepted: 12/23/2023] [Indexed: 01/23/2024]
Abstract
The Gram-negative bacterium Helicobacter pylori is a very successful pathogen, one of the most commonly identified causes of bacterial infections in humans worldwide. H. pylori produces several virulence factors that contribute to its persistence in the hostile host habitat and to its pathogenicity. The most extensively studied are cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA). VacA is present in almost all H. pylori strains. As a secreted multifunctional toxin, it assists bacterial colonization, survival, and proliferation during long-lasting infections. To exert its effect on gastric epithelium and other cell types, VacA undergoes several modifications and crosses multiple membrane barriers. Once inside the gastric epithelial cell, VacA disrupts many cellular-signaling pathways and processes, leading mainly to changes in the efflux of various ions, the depolarization of membrane potential, and perturbations in endocytic trafficking and mitochondrial function. The most notable effect of VacA is the formation of vacuole-like structures, which may lead to apoptosis. This review focuses on the processes involved in VacA secretion, processing, and entry into host cells, with a particular emphasis on the interaction of the mature toxin with host membranes and the formation of transmembrane pores.
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Affiliation(s)
| | - Joanna Skorko-Glonek
- Department of General and Medical Biochemistry, Faculty of Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland;
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Li S, Zhao W, Xia L, Kong L, Yang L. How Long Will It Take to Launch an Effective Helicobacter pylori Vaccine for Humans? Infect Drug Resist 2023; 16:3787-3805. [PMID: 37342435 PMCID: PMC10278649 DOI: 10.2147/idr.s412361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 06/02/2023] [Indexed: 06/22/2023] Open
Abstract
Helicobacter pylori infection often occurs in early childhood, and can last a lifetime if not treated with medication. H. pylori infection can also cause a variety of stomach diseases, which can only be treated with a combination of antibiotics. Combinations of antibiotics can cure H. pylori infection, but it is easy to relapse and develop drug resistance. Therefore, a vaccine is a promising strategy for prevention and therapy for the infection of H. pylori. After decades of research and development, there has been no appearance of any H. pylori vaccine reaching the market, unfortunately. This review summarizes the aspects of candidate antigens, immunoadjuvants, and delivery systems in the long journey of H. pylori vaccine research, and also introduces some clinical trials that have displayed encouraging or depressing results. Possible reasons for the inability of an H. pylori vaccine to be available over the counter are cautiously discussed and some propositions for the future of H. pylori vaccines are outlined.
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Affiliation(s)
- Songhui Li
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009People’s Republic of China
| | - Wenfeng Zhao
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009People’s Republic of China
| | - Lei Xia
- Bloomage Biotechnology Corporation Limited, Jinan, People’s Republic of China
| | - Lingyi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009People’s Republic of China
| | - Lei Yang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009People’s Republic of China
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Imoto I, Oka S, Katsurahara M, Nakamura M, Yasuma T, Akada J, D’Alessandro-Gabazza CN, Toda M, Horiki N, Gabazza EC, Yamaoka Y. Helicobacter pylori infection: is there circulating vacuolating cytotoxin A or cytotoxin-associated gene A protein? Gut Pathog 2022; 14:43. [PMID: 36463198 PMCID: PMC9719618 DOI: 10.1186/s13099-022-00519-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 11/18/2022] [Indexed: 12/07/2022] Open
Abstract
BACKGROUND Helicobacter pylori infection is a well-recognized cause of gastric diseases, including chronic gastritis, peptic ulcer, and gastric cancer. Vacuolating cytotoxin-A (VacA) and cytotoxin-associated gene A protein (CagA) play a role in the pathogenesis of H. pylori-related gastric diseases. Also, extragastric disorders are frequent morbid complications in patients with H. pylori infection. However, the direct pathologic implication of these virulence factors in extragastric manifestations remains unclear. Our hypothesis in the present study is that VacA and CagA released by H. pylori in the gastric mucosa leak into the systemic circulation, and therefore they can be measured in serum. RESULTS Sixty-two subjects were enrolled. They were allocated into the H. pylori-positive and H. pylori-negative groups. VacA and CagA were measured by immunoassays. The serum levels of VacA and CagA above an upper limit cut-off (mean plus two standard deviations of the mean in patients without H. pylori infection) were considered positive for antigen circulating level. Five out of 25 H. pylori-positive patients were positive for both serum VacA and serum CagA. The serum levels of VacA and CagA were significantly correlated with the serum levels of anti- H. pylori antibody and interleukin-12p70 among all H. pylori-positive and H. pylori-negative patients. CONCLUSIONS This study suggests that spill-over of VacA and CagA antigens in the systemic circulation may occur in some patients with H. pylori infection.
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Affiliation(s)
- Ichiro Imoto
- Digestive Endoscopy Center, Department of Internal Medicine, Doshinkai Tohyama Hospital, Minamishinmachi 17-22, Tsu, Mie 514-0043 Japan
| | - Satoko Oka
- Digestive Endoscopy Center, Department of Internal Medicine, Doshinkai Tohyama Hospital, Minamishinmachi 17-22, Tsu, Mie 514-0043 Japan
| | - Masaki Katsurahara
- grid.412075.50000 0004 1769 2015Department of Gastroenterology and Hepatology, Mie University Faculty and Graduate School of Medicine, Mie University Hospital, Edobashi 2-174, Tsu, Mie 514-8507 Japan
| | - Misaki Nakamura
- grid.412075.50000 0004 1769 2015Department of Gastroenterology and Hepatology, Mie University Faculty and Graduate School of Medicine, Mie University Hospital, Edobashi 2-174, Tsu, Mie 514-8507 Japan
| | - Taro Yasuma
- grid.412075.50000 0004 1769 2015Department of Immunology, Mie University Faculty and Graduate School of Medicine, Mie University Hospital, Edobashi 2-174, Tsu, Mie 514-8507 Japan
| | - Junko Akada
- grid.412334.30000 0001 0665 3553Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-Machi, Yufu, Oita 879-5593 Japan
| | - Corina N. D’Alessandro-Gabazza
- grid.412075.50000 0004 1769 2015Department of Immunology, Mie University Faculty and Graduate School of Medicine, Mie University Hospital, Edobashi 2-174, Tsu, Mie 514-8507 Japan
| | - Masaaki Toda
- grid.412075.50000 0004 1769 2015Department of Immunology, Mie University Faculty and Graduate School of Medicine, Mie University Hospital, Edobashi 2-174, Tsu, Mie 514-8507 Japan
| | - Noriyuki Horiki
- grid.412075.50000 0004 1769 2015Department of Gastroenterology and Hepatology, Mie University Faculty and Graduate School of Medicine, Mie University Hospital, Edobashi 2-174, Tsu, Mie 514-8507 Japan
| | - Esteban C. Gabazza
- grid.412075.50000 0004 1769 2015Department of Immunology, Mie University Faculty and Graduate School of Medicine, Mie University Hospital, Edobashi 2-174, Tsu, Mie 514-8507 Japan
| | - Yoshio Yamaoka
- grid.412334.30000 0001 0665 3553Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-Machi, Yufu, Oita 879-5593 Japan ,grid.39382.330000 0001 2160 926XDepartment of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX USA
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Cortactin Promotes Effective AGS Cell Scattering by Helicobacter pylori CagA, but Not Cellular Vacuolization and Apoptosis Induced by the Vacuolating Cytotoxin VacA. Pathogens 2021; 11:pathogens11010003. [PMID: 35055951 PMCID: PMC8777890 DOI: 10.3390/pathogens11010003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 12/15/2022] Open
Abstract
Cortactin is an actin-binding protein and actin-nucleation promoting factor regulating cytoskeletal rearrangements in eukaryotes. Helicobacter pylori is a gastric pathogen that exploits cortactin to its own benefit. During infection of gastric epithelial cells, H. pylori hijacks multiple cellular signaling pathways, leading to the disruption of key cell functions. Two bacterial virulence factors play important roles in this scenario, the vacuolating cytotoxin VacA and the translocated effector protein CagA of the cag type IV secretion system (T4SS). Specifically, by overruling the phosphorylation status of cortactin, H. pylori alternates the activity of molecular interaction partners of this important protein, thereby manipulating the performance of cytoskeletal rearrangements, endosomal trafficking and cell movement. Based on shRNA knockdown and other studies, it was previously reported that VacA utilizes cortactin for its cellular uptake, intracellular travel and induction of apoptosis by a mitochondria-dependent mechanism, while CagA induces cell scattering, motility and elongation. To investigate the role of cortactin in these phenotypes in more detail, we produced a complete knockout mutant of cortactin in the gastric adenocarcinoma cell line AGS by CRISPR-Cas9. These cells were infected with H. pylori wild-type or various isogenic mutant strains. Unexpectedly, cortactin deficiency did not prevent the uptake and formation of VacA-dependent vacuoles, nor the induction of apoptosis by internalized VacA, while the induction of T4SS- and CagA-dependent AGS cell movement and elongation were strongly reduced. Thus, we provide evidence that cortactin is required for the function of internalized CagA, but not VacA.
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Frequency of virulence-associated genotypes of Helicobacter pylori and their correlation with clinical outcome and histological parameters in infected patients. Heliyon 2021; 7:e07610. [PMID: 34355101 PMCID: PMC8322292 DOI: 10.1016/j.heliyon.2021.e07610] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 06/20/2021] [Accepted: 07/14/2021] [Indexed: 11/21/2022] Open
Abstract
Helicobacter pylori (H. pylori) is a gram-negative which can cause several gastroduodenal diseases, including gastritis and peptic ulcer disease (PUD). H. pylori specific genotypes have been related to increased occurrence of gastritis and PUD. The aim of this study was to investigate the clinical relevance of the major virulence factors of H. pylori with clinical outcomes and histological parameters in Iranian patients. Totally, 200 subjects with PUD and gastritis disease who underwent gastroduodenal endoscopy were enrolled in this study. The presence of the cagA, vacA, oipA, babA2, and iceA genes in antral gastric biopsy specimens were determined by polymerase chain reaction (PCR) and the results were compared with clinical outcomes and histological parameters. The frequency of babA2 + , oipA + , vacA s1/m2, and vacA m2 genes was significantly higher in patients with peptic ulcer disease compared with patients with gastritis. In contrast, the frequency of vacA s1/m1 gene was significantly higher in gastritis subjects than PUD subjects. The high-density scores of H. pylori were strongly associated with iceA1 ¯ , babA2 + , and oipA + genes. Additionally, the high polymorphonuclear cell infiltration and high mononuclear cell infiltration scores were strongly associated with the cagA + , iceA1 ¯ , oipA + genes and cagA + , babA2 + , oipA + genes, respectively. Our study indicated that the vacA, babA2, and oipA virulence factors are related to a higher risk of PUD in subjects with H. pylori-infection. Infection with these strains was associated with a more severe gastropathy.
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Mao X, Jakubovics NS, Bächle M, Buchalla W, Hiller KA, Maisch T, Hellwig E, Kirschneck C, Gessner A, Al-Ahmad A, Cieplik F. Colonization of Helicobacter pylori in the oral cavity - an endless controversy? Crit Rev Microbiol 2021; 47:612-629. [PMID: 33899666 DOI: 10.1080/1040841x.2021.1907740] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori is associated with chronic gastritis, gastric or duodenal ulcers, and gastric cancer. Since the oral cavity is the entry port and the first component of the gastrointestinal system, the oral cavity has been discussed as a potential reservoir of H. pylori. Accordingly, a potential oral-oral transmission route of H. pylori raises the question concerning whether close contact such as kissing or sharing a meal can cause the transmission of H. pylori. Therefore, this topic has been investigated in many studies, applying different techniques for detection of H. pylori from oral samples, i.e. molecular techniques, immunological or biochemical methods and traditional culture techniques. While molecular, immunological or biochemical methods usually yield high detection rates, there is no definitive evidence that H. pylori has ever been isolated from the oral cavity. The specificity of those methods may be limited due to potential cross-reactivity, especially with H. pylori-like microorganisms such as Campylobacter spp. Furthermore, the influence of gastroesophageal reflux has not been investigated so far. This review aims to summarize and critically discuss previous studies investigating the potential colonization of H. pylori in the oral cavity and suggest novel research directions for targeting this critical research question.
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Affiliation(s)
- Xiaojun Mao
- Department of Conservative Dentistry and Periodontology, University Hospital Regensburg, Regensburg, Germany
| | - Nicholas S Jakubovics
- Centre for Oral Health Research, School of Dental Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Maria Bächle
- Department of Prosthetic Dentistry, Faculty of Medicine, Center for Dental Medicine, University of Freiburg, Freiburg, Germany
| | - Wolfgang Buchalla
- Department of Conservative Dentistry and Periodontology, University Hospital Regensburg, Regensburg, Germany
| | - Karl-Anton Hiller
- Department of Conservative Dentistry and Periodontology, University Hospital Regensburg, Regensburg, Germany
| | - Tim Maisch
- Department of Dermatology, University Hospital Regensburg, Regensburg, Germany
| | - Elmar Hellwig
- Department of Operative Dentistry and Periodontology, Faculty of Medicine, Center for Dental Medicine, University of Freiburg, Freiburg, Germany
| | | | - André Gessner
- Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany
| | - Ali Al-Ahmad
- Department of Operative Dentistry and Periodontology, Faculty of Medicine, Center for Dental Medicine, University of Freiburg, Freiburg, Germany
| | - Fabian Cieplik
- Department of Conservative Dentistry and Periodontology, University Hospital Regensburg, Regensburg, Germany
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11
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Saric A, Freeman SA. Endomembrane Tension and Trafficking. Front Cell Dev Biol 2021; 8:611326. [PMID: 33490077 PMCID: PMC7820182 DOI: 10.3389/fcell.2020.611326] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 12/09/2020] [Indexed: 12/11/2022] Open
Abstract
Eukaryotic cells employ diverse uptake mechanisms depending on their specialized functions. While such mechanisms vary widely in their defining criteria: scale, molecular machinery utilized, cargo selection, and cargo destination, to name a few, they all result in the internalization of extracellular solutes and fluid into membrane-bound endosomes. Upon scission from the plasma membrane, this compartment is immediately subjected to extensive remodeling which involves tubulation and vesiculation/budding of the limiting endomembrane. This is followed by a maturation process involving concomitant retrograde transport by microtubule-based motors and graded fusion with late endosomes and lysosomes, organelles that support the degradation of the internalized content. Here we review an important determinant for sorting and trafficking in early endosomes and in lysosomes; the control of tension on the endomembrane. Remodeling of endomembranes is opposed by high tension (caused by high hydrostatic pressure) and supported by the relief of tension. We describe how the timely and coordinated efflux of major solutes along the endocytic pathway affords the cell control over such tension. The channels and transporters that expel the smallest components of the ingested medium from the early endocytic fluid are described in detail as these systems are thought to enable endomembrane deformation by curvature-sensing/generating coat proteins. We also review similar considerations for the lysosome where resident hydrolases liberate building blocks from luminal macromolecules and transporters flux these organic solutes to orchestrate trafficking events. How the cell directs organellar trafficking based on the luminal contents of organelles of the endocytic pathway is not well-understood, however, we propose that the control over membrane tension by solute transport constitutes one means for this to ensue.
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Affiliation(s)
- Amra Saric
- Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Spencer A Freeman
- Program in Cell Biology, Peter Gilgan Center for Research and Learning, Hospital for Sick Children, Toronto, ON, Canada.,Department of Biochemistry, University of Toronto, Toronto, ON, Canada
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Soyfoo DM, Doomah YH, Xu D, Zhang C, Sang HM, Liu YY, Zhang GX, Jiang JX, Xu SF. New genotypes of Helicobacter Pylori VacA d-region identified from global strains. BMC Mol Cell Biol 2021; 22:4. [PMID: 33413074 PMCID: PMC7791883 DOI: 10.1186/s12860-020-00338-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 12/16/2020] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Pathogenesis of Helicobacter Pylori (HP) vacuolating toxin A (vacA) depends on polymorphic diversity within the signal (s), middle (m), intermediate (i), deletion (d) and c-regions. These regions show distinct allelic diversity. The s-region, m-region and the c-region (a 15 bp deletion at the 3'-end region of the p55 domain of the vacA gene) exist as 2 types (s1, s2, m1, m2, c1 and c2), while the i-region has 3 allelic types (i1, i2 and i3). The locus of d-region of the vacA gene has also been classified into 2 genotypes, namely d1 and d2. We investigated the "d-region"/"loop region" through bioinformatics, to predict its properties and relation to disease. One thousand two hundred fifty-nine strains from the NCBI nucleotide database and the dryad database with complete vacA sequences were included in the study. The sequences were aligned using BioEdit and analyzed using Lasergene and BLAST. The secondary structure and physicochemical properties of the region were predicted using PredictProtein. RESULTS We identified 31 highly polymorphic genotypes in the "d-region", with a mean length of 34 amino acids (9 ~ 55 amino acids). We further classified the 31 genotypes into 3 main types, namely K-type (strains starting with the KDKP motif in the "d-region"), Q-type (strains starting with the KNQT motif), and E-type (strains starting with the ESKT motif) respectively. The most common type, K-type, is more prevalent in cancer patients (80.87%) and is associated with the s1i1m1c1 genotypes (P < .01). Incidentally, a new region expressing sequence diversity (2 aa deletion) at the C-terminus of the p55 domain of vacA was identified during bioinformatics analysis. CONCLUSIONS Prediction of secondary structures shows that the "d-region" adopts a loop conformation and is a disordered region.
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Affiliation(s)
- Djaleel Muhammad Soyfoo
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yussriya Hanaa Doomah
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dong Xu
- Department of Electrical Engineering and Computer Science, Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Chao Zhang
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, 10021, USA.,Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Huai-Ming Sang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yan-Yan Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guo-Xin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian-Xia Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Shun-Fu Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Segawa T, Ohno Y, Tsuchida S, Ushida K, Yoshioka M. Helicobacter delphinicola sp. nov., isolated from common bottlenose dolphins Tursiops truncatus with gastric diseases. DISEASES OF AQUATIC ORGANISMS 2020; 141:157-169. [PMID: 33030444 DOI: 10.3354/dao03511] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Gastritis and gastric ulcers are well-recognized symptoms in cetaceans, and the genus Helicobacter is considered as the main cause. In this study, we examined the gastric fluid of captive common bottlenose dolphins Tursiops truncatus with gastric diseases in order to isolate the organisms responsible for diagnosis and treatment. Four Gram-negative, rod-shaped isolates (TSBT, TSH1, TSZ, and TSH3) with tightly coiled spirals with 2-4 turns and 2-6 bipolar, sheathed flagella, were obtained from gastric fluids of common bottlenose dolphins with gastric diseases. Phylogenetic analysis, based on 16S rRNA, atpA, and 60 kDa heat-shock protein (hsp60) genes, demonstrated that these isolates form a novel lineage within the genus Helicobacter. Analyses of 16S rRNA, atpA, and hsp60 gene sequences showed that isolate TSBT was most closely related to H. cetorum MIT99-5656T (98.5% similarity), H. pylori ATCC 43504T (76.7% similarity), and H. pylori ATCC 43504T (78.0% similarity), respectively. Type strains of Helicobacter showing resistance to 2% NaCl have not been reported previously; however, these novel isolates were resistant to 2% NaCl. Culture supernatant of some isolates induced intracellular vacuolization in mammalian cultured cells. These data, together with the different morphological and biochemical characteristics of the isolates, reveal that these isolates represent a novel species for which we propose the name Helicobacter delphinicola sp. nov. with type strain TSBT (= JCM 32789T = TSD-183T). Future studies will confirm whether H. delphinicola plays a role in lesion etiopathogenesis in cetaceans.
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Affiliation(s)
- Takao Segawa
- Cetacean Research Center, Graduate School of Bioresources, Mie University, 1577 Kurimamachiya, Tsu, Mie 514-8507, Japan
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Optimized high-purity protein preparation of biologically active recombinant VacA cytotoxin variants from Helicobacter pylori. Protein Expr Purif 2020; 175:105696. [PMID: 32681955 DOI: 10.1016/j.pep.2020.105696] [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: 04/03/2020] [Revised: 06/08/2020] [Accepted: 06/26/2020] [Indexed: 11/23/2022]
Abstract
Vacuolating cytotoxin A (VacA) is a highly polymorphic virulence protein produced by the human gastric pathogen Helicobacter pylori which can cause gastritis, peptic ulcer and gastric cancer. Here, we present an optimized protein preparation of the mature full-length VacA variants (m1-and m2-types) and their 33-kDa N-terminal and 55/59-kDa C-terminal domains as biologically active recombinant proteins fused with an N-terminal His(6) tag. All recombinant VacA constructs were over-expressed in Escherichia coli as insoluble inclusions which were soluble when phosphate buffer (pH 7.4) was supplemented with 5-6 M urea. Upon immobilized-Ni2+ affinity purification under 5-M urea denaturing conditions, homogenous products (>95% purity) of 55/59-kDa domains were consistently obtained while only ~80% purity of both mature VacA variants and the 33-kDa truncate was achieved, thus requiring additional purification by size-exclusion chromatography. After successive refolding via optimized stepwise dialysis, all refolded VacA proteins were proven to possess both cytotoxic and vacuolating activity against cultured human gastric epithelial cells albeit the activity observed for VacA-m2 was lower than the m1-type variant. Such an optimized protocol described herein was effective for production of high-purity recombinant VacA proteins in large amounts (~30-40 mg per liter culture) that would pave the way for further studies on sequence-structure and function relationships of different VacA variants.
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Sit WY, Chen YA, Chen YL, Lai CH, Wang WC. Cellular evasion strategies of Helicobacter pylori in regulating its intracellular fate. Semin Cell Dev Biol 2020; 101:59-67. [PMID: 32033828 PMCID: PMC7102552 DOI: 10.1016/j.semcdb.2020.01.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 01/27/2020] [Indexed: 12/19/2022]
Abstract
Helicobacter pylori colonizes human stomach mucosa and its infection causes gastrointestinal diseases with variable severity. Bacterial infection stimulates autophagy, which is a part of innate immunity used to eliminate intracellular pathogens. Several intracellular bacteria have evolved multipronged strategies to circumvent this conserved system and thereby enhance their chance of intracellular survival. Nonetheless, studies on H. pylori have produced inconsistent results, showing either elevated or reduced clearance efficiency of intracellular bacteria through autophagy. In this review, we summarize recent studies on the mechanisms involved in autophagy induced by H. pylori and the fate of intracellular bacteria.
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Affiliation(s)
- Wei Yang Sit
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan; Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Yu-An Chen
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Lun Chen
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan; Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Chih-Ho Lai
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan; Department of Microbiology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Nursing, Asia University, Taichung, Taiwan; Molecular Infectious Disease Research Center, Department of Pediatrics, Chang Gung Memorial Hospital, Linkuo, Taiwan.
| | - Wen-Ching Wang
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan; Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
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Helicobacter pylori Infection, Virulence Genes' Distribution and Accompanying Clinical Outcomes: The West Africa Situation. BIOMED RESEARCH INTERNATIONAL 2019; 2019:7312908. [PMID: 31886245 PMCID: PMC6925786 DOI: 10.1155/2019/7312908] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 07/18/2019] [Accepted: 08/20/2019] [Indexed: 12/11/2022]
Abstract
Data on Helicobacter pylori (H. pylori) infection and virulence factors in countries across West Africa are scattered. This systematic review seeks to present an update on the status of H. pylori infection focusing on prevalence rate, distribution of virulent genes, and their link to clinical outcomes across countries in the western part of Africa. This information is expected to broaden the knowledge base of clinicians and researchers regarding H. pylori infection and associated virulence factors in West African countries. Search Method. A comprehensive search of the scientific literature in PubMed and ScienceDirect was conducted using the search terms including “Helicobacter pylori infection in West Africa”. Databases were sourced from January 1988 to December 2018. Results. Data on the incidence of H. pylori infection and related pathological factors were found for some countries, whereas others had no information on it. Smoking, alcohol, exposure to high levels of carcinogens and diet were reported to be involved in the pathogenesis of gastroduodenal diseases and gastric cancer. Besides the environmental factors and genetic characteristics, there are important characteristics of H. pylori such as the ability to infect, replicate, and persist in a host that have been associated with the pathogenesis of various gastroduodenal diseases. Concluding Remarks. This systematic search has provided information so far available on H. pylori virulence factors and clinical outcomes in West Africa. Accordingly, this piece has identified gaps in the body of knowledge highlighting the need for more studies to clarify the role of H. pylori virulence factors and associated clinical outcomes in the burden of this bacterial infection in West Africa, as data from these countries do not give the needed direct relation.
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Activity and Functional Importance of Helicobacter pylori Virulence Factors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:35-56. [PMID: 31016624 DOI: 10.1007/5584_2019_358] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori is a very successful Gram-negative pathogen colonizing the stomach of humans worldwide. Infections with this bacterium can generate pathologies ranging from chronic gastritis and peptic ulceration to gastric cancer. The best characterized H. pylori virulence factors that cause direct cell damage include an effector protein encoded by the cytotoxin-associated gene A (CagA), a type IV secretion system (T4SS) encoded in the cag-pathogenicity island (cag PAI), vacuolating cytotoxin A (VacA), γ-glutamyl transpeptidase (GGT), high temperature requirement A (HtrA, a serine protease) and cholesterol glycosyl-transferase (CGT). Since these H. pylori factors are either surface-exposed, secreted or translocated, they can directly interact with host cell molecules and are able to hijack cellular functions. Studies on these bacterial factors have progressed substantially in recent years. Here, we review the current status in the characterization of signaling cascades by these factors in vivo and in vitro, which comprise the disruption of cell-to-cell junctions, induction of membrane rearrangements, cytoskeletal dynamics, proliferative, pro-inflammatory, as well as, pro-apoptotic and anti-apoptotic responses or immune evasion. The impact of these signal transduction modules in the pathogenesis of H. pylori infections is discussed.
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18
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Classification of Helicobacter pylori Virulence Factors: Is CagA a Toxin or Not? Trends Microbiol 2019; 27:731-738. [DOI: 10.1016/j.tim.2019.04.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/16/2019] [Accepted: 04/26/2019] [Indexed: 12/20/2022]
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Gutiérrez-Escobar AJ, Bravo MM, Acevedo O, Backert S. Molecular evolution of the VacA p55 binding domain of Helicobacter pylori in mestizos from a high gastric cancer region of Colombia. PeerJ 2019; 7:e6634. [PMID: 31119065 PMCID: PMC6507892 DOI: 10.7717/peerj.6634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 02/18/2019] [Indexed: 11/20/2022] Open
Abstract
The stomach bacterium Helicobacter pylori is one of the most prevalent pathogens in humans, closely linked with serious diseases such as gastric cancer. The microbe has been associated with its host for more than 100,000 years and escorted modern humans out of Africa. H. pylori is predominantly transmitted within families and dispersed globally, resulting in distinct phylogeographic patterns, which can be utilized to investigate migrations and bioturbation events in human history. Latin America was affected by several human migratory waves due to the Spanish colonisation that drastically changed the genetic load and composition of the bacteria and its host. Genetic evidence indicates that independent evolutionary lines of H. pylori have evolved in mestizos from Colombia and other countries in the region during more than 500 years since colonisation. The vacuolating cytotoxin VacA represents a major virulence factor of the pathogen comprising two domains, p33 and p55, the latter of which is essential for binding to the host epithelial cell. The evolution of the VacA toxin in Colombia has been strongly biased due to the effects of Spanish colonization. However, the variation patterns and microevolution of the p55 domain have not yet been described for this population. In the present study, we determined the genetic polymorphisms and deviations in the neutral model of molecular evolution in the p55 domain of 101 clinical H. pylori isolates collected in Bogotá, a city located in Andean mountains characterized by its high gastric cancer risk and its dominant mestizo population. The microevolutionary patterns of the p55 domain were shaped by recombination, purifying and episodic diversifying positive selection. Furthermore, amino acid positions 261 and 321 in the p55 domain of VacA show a high variability among mestizos clinical subsets, suggesting that natural selection in H. pylori may operate differentially in patients with different gastric diseases.
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Affiliation(s)
- Andrés J. Gutiérrez-Escobar
- Universidad de Ciencias Aplicadas y Ambientales U.D.C.A. Doctorado en Ciencias Biológicas, Pontificia Universidad Javeriana., Bogotá, Colombia
- Division of Microbiology, Department of Biology, Friedrich Alexander University Erlangen/Nuremberg, Erlangen, Germany
| | - María M. Bravo
- Grupo de Investigación en Biología del Cáncer, Instituto Nacional de Cancerología, Bogotá, Colombia
| | - Orlando Acevedo
- Grupo de Biofísica y Bioquímica Estructural, Facultad de Ciencias, Pontifica Universidad Javeriana, Bogotá, Colombia
| | - Steffen Backert
- Division of Microbiology, Department of Biology, Friedrich Alexander University Erlangen/Nuremberg, Erlangen, Germany
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Flores-Treviño CE, Urrutia-Baca VH, Gómez-Flores R, De La Garza-Ramos MA, Sánchez-Chaparro MM, Garza-Elizondo MA. Molecular detection of Helicobacter pylori based on the presence of cagA and vacA virulence genes in dental plaque from patients with periodontitis. J Dent Sci 2019; 14:163-170. [PMID: 31210890 PMCID: PMC6562180 DOI: 10.1016/j.jds.2019.01.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 01/08/2019] [Indexed: 12/15/2022] Open
Abstract
Background/purpose Helicobacter pylori (H. pylori) infection is the most common in the world and is associated with various gastrointestinal pathologies, including chronic gastritis, peptic ulcers, and gastric cancer. The prevalence is associated with socioeconomic conditions, with this infection being more common in developing countries than in developed countries. The presence and permanence of H. pylori in the oral cavity has been reported, but its role is controversial. The aim of this study was to determine the prevalence of H. pylori in dental plaque of patients with periodontitis. Materials and methods A cross-sectional study was carried out and Periodontal Screening and Recording (PSR) index was determined. 38 dental plaque samples were taken and total DNA was extracted and qPCR was performed. Results 60.5% of the samples (n = 23) were positive for the presence of H. pylori by the amplification of the 16S rRNA and vacA genes. In addition, cagA gene was detected in 21.7% (n = 5) of H. pylori-positive. A significant relationship between periodontal status and H. pylori oral infection was found (P ≤ 0.05); patients with initial and moderate periodontitis were the most affected with 39.1% and 30.4%, respectively. Conclusion Our results suggest that the prevalence of H. pylori in the oral cavity could be related to the progression of periodontal disease. Therefore, oral hygiene and treatment for the elimination of oral H. pylori could stop the progression of periodontal disease.
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Affiliation(s)
- Carlos Eduardo Flores-Treviño
- Universidad Autónoma de Nuevo León, Facultad de Odontología y Unidad de Odontología Integral y Especialidades del CIDICS, Av. Dr. Aguirre Pequeño y Silao S/N, Colonia Mitras Centro, CP. 64460, Monterrey, N.L., Mexico.,Universidad Autónoma de Nuevo León, Facultad de Ciencias Biológicas, Departamento de Microbiología e Inmunología, Laboratorio de Inmunología y Virología, Pedro de Alba y Manuel L. Barragán S/N. Cd. Universitaria, CP. 66450, San Nicolás de los Garza, N.L., Mexico
| | - Víctor Hugo Urrutia-Baca
- Universidad Autónoma de Nuevo León, Facultad de Ciencias Biológicas, Departamento de Microbiología e Inmunología, Laboratorio de Inmunología y Virología, Pedro de Alba y Manuel L. Barragán S/N. Cd. Universitaria, CP. 66450, San Nicolás de los Garza, N.L., Mexico
| | - Ricardo Gómez-Flores
- Universidad Autónoma de Nuevo León, Facultad de Ciencias Biológicas, Departamento de Microbiología e Inmunología, Laboratorio de Inmunología y Virología, Pedro de Alba y Manuel L. Barragán S/N. Cd. Universitaria, CP. 66450, San Nicolás de los Garza, N.L., Mexico
| | - Myriam Angélica De La Garza-Ramos
- Universidad Autónoma de Nuevo León, Facultad de Odontología y Unidad de Odontología Integral y Especialidades del CIDICS, Av. Dr. Aguirre Pequeño y Silao S/N, Colonia Mitras Centro, CP. 64460, Monterrey, N.L., Mexico
| | - María Marisela Sánchez-Chaparro
- Universidad Autónoma de Nuevo León, Facultad de Ciencias Biológicas, Departamento de Microbiología e Inmunología, Laboratorio de Inmunología y Virología, Pedro de Alba y Manuel L. Barragán S/N. Cd. Universitaria, CP. 66450, San Nicolás de los Garza, N.L., Mexico
| | - Mario Alberto Garza-Elizondo
- Universidad Autónoma de Nuevo León, Facultad de Odontología y Unidad de Odontología Integral y Especialidades del CIDICS, Av. Dr. Aguirre Pequeño y Silao S/N, Colonia Mitras Centro, CP. 64460, Monterrey, N.L., Mexico
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Cryo-EM structures of Helicobacter pylori vacuolating cytotoxin A oligomeric assemblies at near-atomic resolution. Proc Natl Acad Sci U S A 2019; 116:6800-6805. [PMID: 30894496 PMCID: PMC6452728 DOI: 10.1073/pnas.1821959116] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Helicobacter pylori infects nearly half of the world’s population and is the primary cause of various gastric diseases. It has evolved various virulence factors to aid its host colonization and infection, including the vacuolating cytotoxin A (VacA) that is responsible for the pathogenesis of H. pylori-related diseases. Here, we resolve multiple structures of the water-soluble VacA oligomeric assemblies using cryoelectron microscopy (cryo-EM) at near-atomic resolution. These studies suggest a model of structural changes of functional VacA hexamer needed for the pore-formation process across the membrane and highlight the capability of cryo-EM to resolve multiple structure snapshots from a single specimen at near-atomic resolution. Human gastric pathogen Helicobacter pylori (H. pylori) is the primary risk factor for gastric cancer and is one of the most prevalent carcinogenic infectious agents. Vacuolating cytotoxin A (VacA) is a key virulence factor secreted by H. pylori and induces multiple cellular responses. Although structural and functional studies of VacA have been extensively performed, the high-resolution structure of a full-length VacA protomer and the molecular basis of its oligomerization are still unknown. Here, we use cryoelectron microscopy to resolve 10 structures of VacA assemblies, including monolayer (hexamer and heptamer) and bilayer (dodecamer, tridecamer, and tetradecamer) oligomers. The models of the 88-kDa full-length VacA protomer derived from the near-atomic resolution maps are highly conserved among different oligomers and show a continuous right-handed β-helix made up of two domains with extensive domain–domain interactions. The specific interactions between adjacent protomers in the same layer stabilizing the oligomers are well resolved. For double-layer oligomers, we found short- and/or long-range hydrophobic interactions between protomers across the two layers. Our structures and other previous observations lead to a mechanistic model wherein VacA hexamer would correspond to the prepore-forming state, and the N-terminal region of VacA responsible for the membrane insertion would undergo a large conformational change to bring the hydrophobic transmembrane region to the center of the oligomer for the membrane channel formation.
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Helicobacter pylori infection in children: an overview of diagnostic methods. Eur J Clin Microbiol Infect Dis 2019; 38:1035-1045. [PMID: 30734129 DOI: 10.1007/s10096-019-03502-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 01/31/2019] [Indexed: 12/14/2022]
Abstract
Children differ from adults regarding Helicobacter pylori (H. pylori) infection in many terms. H. pylori infection represents a key factor in the pathogenesis of duodenal ulcer and chronic gastritis in children. H. pylori infection causes some extraintestinal diseases as well as gastrointestinal diseases. Although, among these illnesses in children, symptoms like recurrent abdominal pain are not specific. Moreover, the role of the pathogen in the growth faltering, iron deficiency anemia, and asthma still remains controversial. A reliable method to detect H. pylori infection is a crucial issue, sand is still a matter of active debate. The tests applied for H. pylori diagnosis are grouped as either invasive or non-invasive methods. Invasive methods consist of endoscopic evaluation, the rapid urease test (RUT), histology, and bacterial culture. Non-invasive tests include the urea breath test (UBT), stool antigen test (SAT), serology, and molecular diagnostic approaches. Use of endoscopy is a pre-requisite for all invasive methods and poses difficulties in children as it is a difficult procedure and requires patient's cooperation. For this reason, the non-invasive tests have been commonly used in children, although their accuracy is not very reliable in some cases. Invasive tests may be opted to confirm the diagnosis as and when needed. This review presents the diagnostic tests used to detect H. pylori infection in children.
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Chauhan N, Tay ACY, Marshall BJ, Jain U. Helicobacter pylori VacA, a distinct toxin exerts diverse functionalities in numerous cells: An overview. Helicobacter 2019; 24:e12544. [PMID: 30324717 DOI: 10.1111/hel.12544] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 08/21/2018] [Accepted: 09/06/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Helicobacter pylori, gastric cancer-causing bacteria, survive in their gastric environment of more than 50% of the world population. The presence of H. pylori in the gastric vicinity promotes the development of various diseases including peptic ulcer and gastric carcinoma. H. pylori produce and secret Vacuolating cytotoxin A (VacA), a major toxin facilitating the bacteria against the host defense system. The toxin causes multiple effects in epithelial cells and immune cells, especially T cells, B cells, and Macrophages. METHODS This review describes the diverse functionalities of protein toxin VacA. The specific objective of this review is to address the overall structure, mechanism, and functions of VacA in various cell types. The recent advancements are summarized and discussed and thus conclusion is drawn based on the overall reported evidences. RESULTS The searched articles on H. pylori VacA were evaluated and limited up to 66 articles for this review. The articles were divided into four major categories including articles on vacA gene, VacA toxin, distinct effects of VacA toxin, and their effects on various cells. Based on these studies, the review article was prepared. CONCLUSIONS This review describes an overview of how VacA is secreted by H. pylori and contributes to colonization and virulence in multiple ways by affecting epithelial cells, T cells, Dendritic cells, B cells, and Macrophages. The reported evidence suggests that the comprehensive outlook need to be developed for understanding distinctive functionalities of VacA.
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Affiliation(s)
- Nidhi Chauhan
- Amity Institute of Nanotechnology, Amity University, Noida, Uttar Pradesh, India
| | - Alfred Chin Yen Tay
- The Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Nedlands, Western Australia, Australia.,Shenzhen Dapeng New District Kuichong People Hospital, Shenzhen, Guangdong, China
| | - Barry J Marshall
- The Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Utkarsh Jain
- Amity Institute of Nanotechnology, Amity University, Noida, Uttar Pradesh, India
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Abstract
BACKGROUND In adults, Helicobacter pylori is aetiologically associated with peptic ulcer disease and gastric cancer. However, the relationship between this bacteria and gastro-intestinal symptoms in children is less clear. AIMS To review the recent literature on H. pylori in children and to outline the approach to diagnosis and management. METHODS The English language literature was searched for articles on H. pylori in children. Special attention was paid to prevalence, diagnosis and management pertinent to low- and middle-income countries (LMIC). RESULTS Although the prevalence of H. pylori is 60-80% in LMIC, only 5% of infected children develop peptic ulcer disease. The virulence of the organism determines the outcome. There is a suggestion that H. pylori causes iron deficiency anaemia, growth retardation and idiopathic thrombocytopenic purpura, but the evidence is not sufficiently strong to justify screening. There is no evidence to suggest a link between H. pylori infection and recurrent abdominal pain. Endoscopy (with invasive tests) is the preferred method of investigation as the primary goal is to determine the underlying cause of the symptoms. Children with H. pylori-related diseases should be treated with a standard triple-drug regimen consisting of a protein pump inhibitor and two antibiotics for 10-14 days. All treated patients should be monitored for eradication with non-invasive tests such as the urea (13-C) breath test or stool antigen tests. CONCLUSIONS Although H. pylori infection is common in LMIC, most children are asymptomatic. There is no association between H. pylori and recurrent abdominal pain. Invasive tests are preferred for diagnosis and a triple-drug regimen is the treatment of choice.
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Affiliation(s)
- Ujjal Poddar
- a Department of Paediatric Gastroenterology , Sanjay Gandhi Postgraduate Institute of Medical Sciences , Lucknow , India
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Helicobacter pylori, Peptic Ulcer Disease and Gastric Cancer. GASTROINTESTINAL DISEASES AND THEIR ASSOCIATED INFECTIONS 2019. [DOI: 10.1016/b978-0-323-54843-4.00002-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Whitmire JM, Merrell DS. Helicobacter pylori Genetic Polymorphisms in Gastric Disease Development. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:173-194. [DOI: 10.1007/5584_2019_365] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Kim IJ, Lee J, Oh SJ, Yoon MS, Jang SS, Holland RL, Reno ML, Hamad MN, Maeda T, Chung HJ, Chen J, Blanke SR. Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1. Cell Host Microbe 2018; 23:583-593.e8. [PMID: 29746831 DOI: 10.1016/j.chom.2018.04.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 03/15/2018] [Accepted: 04/17/2018] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori (Hp) vacuolating cytotoxin (VacA) is a bacterial exotoxin that enters host cells and induces mitochondrial dysfunction. However, the extent to which VacA-dependent mitochondrial perturbations affect overall cellular metabolism is poorly understood. We report that VacA perturbations in mitochondria are linked to alterations in cellular amino acid homeostasis, which results in the inhibition of mammalian target of rapamycin complex 1 (mTORC1) and subsequent autophagy. mTORC1, which regulates cellular metabolism during nutrient stress, is inhibited during Hp infection by a VacA-dependent mechanism. This VacA-dependent inhibition of mTORC1 signaling is linked to the dissociation of mTORC1 from the lysosomal surface and results in activation of cellular autophagy through the Unc 51-like kinase 1 (Ulk1) complex. VacA intoxication results in reduced cellular amino acids, and bolstering amino acid pools prevents VacA-mediated mTORC1 inhibition. Overall, these studies support a model that Hp modulate host cell metabolism through the action of VacA at mitochondria.
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Affiliation(s)
- Ik-Jung Kim
- Department of Microbiology, University of Illinois, Urbana, IL 61801, USA
| | - Jeongmin Lee
- Department of Biochemistry, University of Illinois, Urbana, IL 61801, USA
| | - Seung J Oh
- Department of Biochemistry, University of Illinois, Urbana, IL 61801, USA
| | - Mee-Sup Yoon
- Department of Cell and Developmental Biology, University of Illinois, Urbana, IL 61801, USA; Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea
| | - Sung-Soo Jang
- Department of Molecular and Integrative Physiology, University of Illinois, Urbana, IL 61801, USA
| | - Robin L Holland
- Department of Pathobiology, University of Illinois, Urbana, IL 61801, USA
| | - Michael L Reno
- Department of Microbiology, University of Illinois, Urbana, IL 61801, USA
| | - Mohammed N Hamad
- Department of Microbiology, University of Illinois, Urbana, IL 61801, USA
| | - Tatsuya Maeda
- Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Hee Jung Chung
- Department of Molecular and Integrative Physiology, University of Illinois, Urbana, IL 61801, USA
| | - Jie Chen
- Department of Cell and Developmental Biology, University of Illinois, Urbana, IL 61801, USA
| | - Steven R Blanke
- Department of Microbiology, University of Illinois, Urbana, IL 61801, USA; Institute for Genomic Biology, University of Illinois, Urbana, IL 61801, USA; Lead Contact.
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Abstract
Helicobacter pylori, a Gram-negative bacterium, is a well-known risk factor for gastric cancer. H. pylori vacuolating cytotoxin A (VacA) is a secreted pore-forming toxin that induces a wide range of cellular responses. Like many other bacterial toxins, VacA has been hypothesized to utilize lipid rafts to gain entry into host cells. Here, we used giant plasma membrane vesicles (GPMVs) as a model system to understand the preferential partitioning of VacA into lipid rafts. We show that a wild-type (WT) toxin predominantly associates with the raft phase. Acid activation of VacA enhances binding of the toxin to GPMVs but is not required for raft partitioning. VacA mutant proteins with alterations at the amino terminus (resulting in impaired membrane channel formation) and a nonoligomerizing VacA mutant protein retain the ability to preferentially associate with lipid rafts. Consistent with these results, the isolated VacA p55 domain was capable of binding to lipid rafts. We conclude that the affinity of VacA for rafts is independent of its capacity to oligomerize or form membrane channels.
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Influence of Helicobacter pylori virulence factors CagA and VacA on pathogenesis of gastrointestinal disorders. Microb Pathog 2018; 117:43-48. [PMID: 29432909 DOI: 10.1016/j.micpath.2018.02.016] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 01/07/2018] [Accepted: 02/08/2018] [Indexed: 12/23/2022]
Abstract
Helicobacter Pylori (H. pylori) is a gram-negative bacteria infecting numerous people all over the world. It has been established that H. pylori play an important role in pathogenesis of gastritis, peptic ulcer and gastric cancer. Pathogenic features of this bacterium are mainly attributes to the existence of pathogenic islands (PAI) genes. The most known genes in these islands are cytotoxin-associated gene A (CagA) and vacuolating cytotoxin gene (VacA). Most studies demonstrated various frequency of CagA and VacA in patient with peptic ulcer or gastritis in different countries. This variation in CagA and VacA frequency may be due to the capability of this bacterium to be genetically versatile and can alter the expression of these genes with geographic diversity. Although H. pylori infection is not usually associated with any clinical symptoms, but sometimes leads to inflammation in gastrointestinal system and resulted in peptic ulcer and gastric cancer. In this regard, this review will illustrate the importance of Helicobacter pylori in pathogenesis of gastrointestinal disorders with focusing on CagA and VacA virulence factors.
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Necchi V, Sommi P, Vanoli A, Fiocca R, Ricci V, Solcia E. Natural history of Helicobacter pylori VacA toxin in human gastric epithelium in vivo: vacuoles and beyond. Sci Rep 2017; 7:14526. [PMID: 29109534 PMCID: PMC5673961 DOI: 10.1038/s41598-017-15204-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 10/23/2017] [Indexed: 02/08/2023] Open
Abstract
Uptake, intracellular trafficking and pathologic effects of VacA toxin from Helicobacter pylori have been widely investigated in vitro. However, no systematic analysis investigated VacA intracellular distribution and fate in H. pylori-infected human gastric epithelium in vivo, using ultrastructural immunocytochemistry that combines precise toxin localization with analysis of the overall cell ultrastructure and intercompartimental/interorganellar relationships. By immunogold procedure, in this study we investigated gastric biopsies taken from dyspeptic patients to characterize the overall toxin’s journey inside human gastric epithelial cells in vivo. Endocytic pits were found to take up VacA at sites of bacterial adhesion, leading to a population of peripheral endosomes, which in deeper (juxtanuclear) cytoplasm enlarged and fused each other to form large VacA-containing vacuoles (VCVs). These directly opened into endoplasmic reticulum (ER) cisternae, which in turn enveloped mitochondria and contacted the Golgi apparatus. In all such organelles we found toxin molecules, often coupled with structural damage. These findings suggest direct toxin transfer from VCVs to other target organelles such as ER/Golgi and mitochondria. VacA-induced cytotoxic changes were associated with the appearance of auto(phago)lysosomes containing VacA, polyubiquitinated proteins, p62/SQSTM1 protein, cathepsin D, damaged mitochondria and bacterial remnants, thus leading to persistent cell accumulation of degradative products.
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Affiliation(s)
- Vittorio Necchi
- Department of Molecular Medicine, Pathologic Anatomy and Human Physiology Units, University of Pavia, Pavia, Italy.,Centro Grandi Strumenti, University of Pavia, Pavia, Italy
| | - Patrizia Sommi
- Department of Molecular Medicine, Pathologic Anatomy and Human Physiology Units, University of Pavia, Pavia, Italy
| | - Alessandro Vanoli
- Department of Molecular Medicine, Pathologic Anatomy and Human Physiology Units, University of Pavia, Pavia, Italy
| | - Roberto Fiocca
- Department of Surgical and Diagnostic Sciences, Pathology Unit, University of Genova and IRCCS S. Martino, Genova, Italy
| | - Vittorio Ricci
- Department of Molecular Medicine, Pathologic Anatomy and Human Physiology Units, University of Pavia, Pavia, Italy.
| | - Enrico Solcia
- Department of Molecular Medicine, Pathologic Anatomy and Human Physiology Units, University of Pavia, Pavia, Italy.,Pathologic Anatomy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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McClain MS, Beckett AC, Cover TL. Helicobacter pylori Vacuolating Toxin and Gastric Cancer. Toxins (Basel) 2017; 9:toxins9100316. [PMID: 29023421 PMCID: PMC5666363 DOI: 10.3390/toxins9100316] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 10/03/2017] [Accepted: 10/05/2017] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori VacA is a channel-forming toxin unrelated to other known bacterial toxins. Most H. pylori strains contain a vacA gene, but there is marked variation among strains in VacA toxin activity. This variation is attributable to strain-specific variations in VacA amino acid sequences, as well as variations in the levels of VacA transcription and secretion. In this review, we discuss epidemiologic studies showing an association between specific vacA allelic types and gastric cancer, as well as studies that have used animal models to investigate VacA activities relevant to gastric cancer. We also discuss the mechanisms by which VacA-induced cellular alterations may contribute to the pathogenesis of gastric cancer.
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Affiliation(s)
- Mark S McClain
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
| | - Amber C Beckett
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
| | - Timothy L Cover
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA.
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Li Q, Liu J, Gong Y, Yuan Y. Serum VacA antibody is associated with risks of peptic ulcer and gastric cancer: A meta-analysis. Microb Pathog 2016; 99:220-228. [PMID: 27568203 DOI: 10.1016/j.micpath.2016.08.030] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 07/27/2016] [Accepted: 08/23/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND Increasing studies have investigated the relationship between the status of H. pylori vacA antibody and risks of peptic ulcer disease (PUD) and gastric cancer (GC). However, the results were controversial. The aim of this meta-analysis is to clarify whether serum vacA antibody is associated with risks of PUD and GC. METHODS Databases including PubMed, Embase, Web of knowledge, Wanfang, Chinese National Knowledge Infrastructure (CNKI), OVID, Karger and Scopus were systematically searched for potentially eligible literature. Odds ratios (OR) and their 95% confidence interval (CI) were adopted to assess the strength of association. RESULTS Serum VacA antibody was associated with increased risk of PUD compared with gastritis/functional dyspepsia (FD) (OR = 1.96, 95%CI = 1.56-2.46, P < 0.001). Serum VacA antibody was significantly associated with increased risk of gastric ulcer (GU) and duodenal ulcer (DU) compared with gastritis/FD (GU: OR = 1.64, 95%CI = 1.02-2.62, P = 0.042; DU: OR = 2.06, 95%CI = 1.50-2.84, P < 0.001, respectively). Significant increased risk of GC was found in serum VacA antibody positive subjects compared with serum VacA antibody negative individuals (OR = 2.78, 95%CI = 1.98-3.89, P < 0.001). There was no significant publication bias in all of the comparisons. CONCLUSIONS Serum VacA antibody was significantly associated with increased risks of peptic ulcer disease, gastric ulcer and duodenal ulcer compared with gastritis and functional dyspepsia controls. Significant association was also found between serum VacA antibody and gastric cancer risk. Serum VacA antibody might be a potential biomarker for the prediction of risks of PUD and GC.
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Affiliation(s)
- Qiuping Li
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Jingwei Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Yuehua Gong
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China.
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China.
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A Nonoligomerizing Mutant Form of Helicobacter pylori VacA Allows Structural Analysis of the p33 Domain. Infect Immun 2016; 84:2662-70. [PMID: 27382020 PMCID: PMC4995914 DOI: 10.1128/iai.00254-16] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 06/24/2016] [Indexed: 12/17/2022] Open
Abstract
Helicobacter pylori secretes a pore-forming VacA toxin that has structural features and activities substantially different from those of other known bacterial toxins. VacA can assemble into multiple types of water-soluble flower-shaped oligomeric structures, and most VacA activities are dependent on its capacity to oligomerize. The 88-kDa secreted VacA protein can undergo limited proteolysis to yield two domains, designated p33 and p55. The p33 domain is required for membrane channel formation and intracellular toxic activities, and the p55 domain has an important role in mediating VacA binding to cells. Previous studies showed that the p55 domain has a predominantly β-helical structure, but no structural data are available for the p33 domain. We report here the purification and analysis of a nonoligomerizing mutant form of VacA secreted by H. pylori The nonoligomerizing 88-kDa mutant protein retains the capacity to enter host cells but lacks detectable toxic activity. Analysis of crystals formed by the monomeric protein reveals that the β-helical structure of the p55 domain extends into the C-terminal portion of p33. Fitting the p88 structural model into an electron microscopy map of hexamers formed by wild-type VacA (predicted to be structurally similar to VacA membrane channels) reveals that p55 and the β-helical segment of p33 localize to peripheral arms but do not occupy the central region of the hexamers. We propose that the amino-terminal portion of p33 is unstructured when VacA is in a monomeric form and that it undergoes a conformational change during oligomer assembly.
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Ahmad SA, Xia BT, Bailey CE, Abbott DE, Helmink BA, Daly MC, Thota R, Schlegal C, Winer LK, Ahmad SA, Al Humaidi AH, Parikh AA. An update on gastric cancer. Curr Probl Surg 2016; 53:449-90. [PMID: 27671911 DOI: 10.1067/j.cpsurg.2016.08.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 08/03/2016] [Indexed: 12/11/2022]
Affiliation(s)
- Syed A Ahmad
- Division of Surgical Oncology, University of Cincinnati Cancer Institute, University of Cincinnati College of Medicine, Cincinnati, OH.
| | - Brent T Xia
- Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH
| | - Christina E Bailey
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Daniel E Abbott
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Beth A Helmink
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Meghan C Daly
- Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH
| | - Ramya Thota
- Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN
| | - Cameron Schlegal
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Leah K Winer
- Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH
| | | | - Ali H Al Humaidi
- Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH
| | - Alexander A Parikh
- Division of Hepatobiliary, Pancreas and Gastrointestinal Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN
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Nair MRB, Chouhan D, Sen Gupta S, Chattopadhyay S. Fermented Foods: Are They Tasty Medicines for Helicobacter pylori Associated Peptic Ulcer and Gastric Cancer? Front Microbiol 2016; 7:1148. [PMID: 27504109 PMCID: PMC4958626 DOI: 10.3389/fmicb.2016.01148] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 07/11/2016] [Indexed: 12/21/2022] Open
Abstract
More than a million people die every year due to gastric cancer and peptic ulcer. Helicobacter pylori infection in stomach is the most important reason for these diseases. Interestingly, only 10-20% of the H. pylori infected individuals suffer from these gastric diseases and rest of the infected individuals remain asymptomatic. The genotypes of H. pylori, host genetic background, lifestyle including smoking and diet may determine clinical outcomes. People from different geographical regions have different food habits, which also include several unique fermented products of plant and animal origins. When consumed raw, the fermented foods bring in fresh inocula of microbes to gastrointestinal tract and several strains of these microbes, like Lactobacillus and Saccharomyces are known probiotics. In vitro and in vivo experiments as well as clinical trials suggest that several probiotics have anti-H. pylori effects. Here we discuss the possibility of using natural probiotics present in traditional fermented food and beverages to obtain protection against H. pylori induced gastric diseases.
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Affiliation(s)
| | | | | | - Santanu Chattopadhyay
- Microbiome Research Facility, Microbiome Biology, Rajiv Gandhi Centre for BiotechnologyTrivandrum, India
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36
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Ricci V. Relationship between VacA Toxin and Host Cell Autophagy in Helicobacter pylori Infection of the Human Stomach: A Few Answers, Many Questions. Toxins (Basel) 2016; 8:toxins8070203. [PMID: 27376331 PMCID: PMC4963836 DOI: 10.3390/toxins8070203] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 06/14/2016] [Accepted: 06/17/2016] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori is a Gram-negative bacterium that colonizes the stomach of about half the global population and represents the greatest risk factor for gastric malignancy. The relevance of H. pylori for gastric cancer development is equivalent to that of tobacco smoking for lung cancer. VacA toxin seems to play a pivotal role in the overall strategy of H. pylori towards achieving persistent gastric colonization. This strategy appears to involve the modulation of host cell autophagy. After an overview of autophagy and its role in infection and carcinogenesis, I critically review current knowledge about the action of VacA on host cell autophagy during H. pylori infection of the human stomach. Although VacA is a key player in modulation of H. pylori-induced autophagy, a few discrepancies in the data are also evident and many questions remain to be answered. We are thus still far from a definitive understanding of the molecular mechanisms through which VacA affects autophagy and the consequences of this toxin action on the overall pathogenic activity of H. pylori.
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Affiliation(s)
- Vittorio Ricci
- Department of Molecular Medicine, Human Physiology Unit, University of Pavia Medical School, Via Forlanini 6, 27100 Pavia, Italy.
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Foegeding NJ, Caston RR, McClain MS, Ohi MD, Cover TL. An Overview of Helicobacter pylori VacA Toxin Biology. Toxins (Basel) 2016; 8:toxins8060173. [PMID: 27271669 PMCID: PMC4926140 DOI: 10.3390/toxins8060173] [Citation(s) in RCA: 147] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Revised: 05/18/2016] [Accepted: 05/27/2016] [Indexed: 12/11/2022] Open
Abstract
The VacA toxin secreted by Helicobacter pylori enhances the ability of the bacteria to colonize the stomach and contributes to the pathogenesis of gastric adenocarcinoma and peptic ulcer disease. The amino acid sequence and structure of VacA are unrelated to corresponding features of other known bacterial toxins. VacA is classified as a pore-forming toxin, and many of its effects on host cells are attributed to formation of channels in intracellular sites. The most extensively studied VacA activity is its capacity to stimulate vacuole formation, but the toxin has many additional effects on host cells. Multiple cell types are susceptible to VacA, including gastric epithelial cells, parietal cells, T cells, and other types of immune cells. This review focuses on the wide range of VacA actions that are detectable in vitro, as well as actions of VacA in vivo that are relevant for H. pylori colonization of the stomach and development of gastric disease.
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Affiliation(s)
- Nora J Foegeding
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
| | - Rhonda R Caston
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
| | - Mark S McClain
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
| | - Melanie D Ohi
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
- Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA.
| | - Timothy L Cover
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA.
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Figura N, Marano L, Moretti E, Ponzetto A. Helicobacter pylori infection and gastric carcinoma: Not all the strains and patients are alike. World J Gastrointest Oncol 2016; 8:40-54. [PMID: 26798436 PMCID: PMC4714145 DOI: 10.4251/wjgo.v8.i1.40] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Revised: 10/06/2015] [Accepted: 11/03/2015] [Indexed: 02/05/2023] Open
Abstract
Gastric carcinoma (GC) develops in only 1%-3% of Helicobacter pylori (H. pylori) infected people. The role in GC formation of the bacterial genotypes, gene polymorphisms and host's factors may therefore be important. The risk of GC is enhanced when individuals are infected by strains expressing the oncoprotein CagA, in particular if CagA has a high number of repeats containing the EPIYA sequence in its C'-terminal variable region or particular amino acid sequences flank the EPIYA motifs. H. pylori infection triggers an inflammatory response characterised by an increased secretion of some chemokines by immunocytes and colonised gastric epithelial cells; these molecules are especially constituted by proteins composing the interleukin-1beta (IL-1β) group and tumour necrosis factor-alpha (TNF-α). Polymorphisms in the promoter regions of genes encoding these molecules, could account for high concentrations of IL-1β and TNF-α in the gastric mucosa, which may cause hypochlorhydria and eventually GC. Inconsistent results have been attained with other haplotypes of inflammatory and anti-inflammatory cytokines. Genomic mechanisms of GC development are mainly based on chromosomal or microsatellite instability (MSI) and deregulation of signalling transduction pathways. H. pylori infection may induce DNA instability and breaks of double-strand DNA in gastric mucocytes. Different H. pylori strains seem to differently increase the risk of cancer development run by the host. Certain H. pylori genotypes (such as the cagA positive) induce high degrees of chronic inflammation and determine an increase of mutagenesis rate, oxidative-stress, mismatch repair mechanisms, down-regulation of base excision and genetic instability, as well as generation of reactive oxygen species that modulate apoptosis; these phenomena may end to trigger or concur to GC development.
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Cover TL, Holland RL, Blanke SR. Helicobacter pylori Vacuolating Toxin. HELICOBACTER PYLORI RESEARCH 2016:113-141. [DOI: 10.1007/978-4-431-55936-8_5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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40
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Effects of crude extracted proteins from supernatant of BCF-P and EGF on acid secretion. Mol Cell Toxicol 2015. [DOI: 10.1007/s13273-015-0034-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Kern B, Jain U, Utsch C, Otto A, Busch B, Jiménez-Soto L, Becher D, Haas R. Characterization of Helicobacter pylori VacA-containing vacuoles (VCVs), VacA intracellular trafficking and interference with calcium signalling in T lymphocytes. Cell Microbiol 2015; 17:1811-32. [PMID: 26078003 DOI: 10.1111/cmi.12474] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Revised: 05/27/2015] [Accepted: 06/11/2015] [Indexed: 12/11/2022]
Abstract
The human pathogen Helicobacter pylori colonizes half of the global population. Residing at the stomach epithelium, it contributes to the development of diseases such as gastritis, duodenal and gastric ulcers, and gastric cancer. A major factor is the secreted vacuolating toxin VacA, which forms anion-selective channels in the endosome membrane that cause the compartment to swell, but the composition and purpose of the resulting VacA-containing vacuoles (VCVs) are still unknown. VacA exerts influence on the host immune response in various ways, including inhibition of T-cell activation and proliferation and suppression of the host immune response. In this study, for the first time the composition of VCVs from T cells was comprehensively analysed to investigate VCV function. VCVs were successfully isolated via immunomagnetic separation, and the purified vacuoles were analysed by mass spectrometry. We detected a set of 122 VCV-specific proteins implicated among others in immune response, cell death and cellular signalling processes, all of which VacA is known to influence. One of the individual proteins studied further was stromal interaction molecule (STIM1), a calcium sensor residing in the endoplasmic reticulum (ER) that is important in store-operated calcium entry. Live cell imaging microscopy data demonstrated colocalization of VacA with STIM1 in the ER and indicated that VacA may interfere with the movement of STIM1 towards the plasma membrane-localized calcium release activated calcium channel protein ORAI1 in response to Ca(2+) store depletion. Furthermore, VacA inhibited the increase of cytosolic-free Ca(2+) in the Jurkat E6-1 T-cell line and human CD4(+) T cells. The presence of VacA in the ER and its trafficking to the Golgi apparatus was confirmed in HeLa cells, identifying these two cellular compartments as novel VacA target structures.
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Affiliation(s)
- Beate Kern
- Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität, München, Germany
| | - Utkarsh Jain
- Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität, München, Germany
| | - Ciara Utsch
- Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität, München, Germany
| | - Andreas Otto
- Institut für Mikrobiologie, Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany
| | - Benjamin Busch
- Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität, München, Germany
| | - Luisa Jiménez-Soto
- Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität, München, Germany
| | - Dörte Becher
- Institut für Mikrobiologie, Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany
| | - Rainer Haas
- Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität, München, Germany.,German Center for Infection Research (DZIF), Munich, Germany
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Florey O, Gammoh N, Kim SE, Jiang X, Overholtzer M. V-ATPase and osmotic imbalances activate endolysosomal LC3 lipidation. Autophagy 2015; 11:88-99. [PMID: 25484071 PMCID: PMC4502810 DOI: 10.4161/15548627.2014.984277] [Citation(s) in RCA: 164] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Revised: 06/25/2014] [Accepted: 07/08/2014] [Indexed: 02/01/2023] Open
Abstract
Recently a noncanonical activity of autophagy proteins has been discovered that targets lipidation of microtubule-associated protein 1 light chain 3 (LC3) onto macroendocytic vacuoles, including macropinosomes, phagosomes, and entotic vacuoles. While this pathway is distinct from canonical autophagy, the mechanism of how these nonautophagic membranes are targeted for LC3 lipidation remains unclear. Here we present evidence that this pathway requires activity of the vacuolar-type H(+)-ATPase (V-ATPase) and is induced by osmotic imbalances within endolysosomal compartments. LC3 lipidation by this mechanism is induced by treatment of cells with the lysosomotropic agent chloroquine, and through exposure to the Heliobacter pylori pore-forming toxin VacA. These data add novel mechanistic insights into the regulation of noncanonical LC3 lipidation and its associated processes, including LC3-associated phagocytosis (LAP), and demonstrate that the widely and therapeutically used drug chloroquine, which is conventionally used to inhibit autophagy flux, is an inducer of LC3 lipidation.
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Key Words
- ATG, autophagy-related
- Baf, bafilomycin A1
- CALCOCO2/NDP52, calcium binding and coiled-coil domain 2
- CQ, chloroquine
- ConA, concanamycin A
- FYCO1, FYVE and coiled-coil domain containing 1
- GFP, green fluorescent protein
- Helicobacter pylori
- LAMP1, lysosomal-associated membrane protein 1
- LAP
- LAP, LC3-associated phagocytosis
- LC3
- MAP1LC3/LC3, microtubule-associated protein 1 light chain 3
- MTOR, mechanistic target of rapamycin
- PIK3C3/VPS34, phosphatidylinositol 3-kinase
- PtdIns3K, phosphatidylinositol 3-kinase
- PtdIns3P, phosphatidylinositol 3-phosphate
- RB1CC1/FIP200, RB1-inducible coiled-coil 1
- SQSTM1/p62, sequestosome 1
- TEM, transmission electron microscopy
- TLR, toll-like receptor
- ULK1/2, unc-51 like autophagy activating kinase 1/2
- V-ATPase
- V-ATPase, vacuolar-type H+-ATPase
- VacA, vacuolating toxin A
- autophagy
- catalytic subunit type 3
- chloroquine
- entosis
- lysosome
- phagocytosis
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Affiliation(s)
- Oliver Florey
- Cell Biology Program; Memorial Sloan-Kettering Cancer Center; New York, NY USA
- Signalling Program; The Babraham Institute; Cambridge, UK
| | - Noor Gammoh
- Cell Biology Program; Memorial Sloan-Kettering Cancer Center; New York, NY USA
- Edinburgh Cancer Research UK Center; Institute of Genetics and Molecular Medicine; University of Edinburgh; Edinburgh, UK
| | - Sung Eun Kim
- Cell Biology Program; Memorial Sloan-Kettering Cancer Center; New York, NY USA
- BCMB Allied Program; Weill Cornell Medical College; New York, NY USA
| | - Xuejun Jiang
- Cell Biology Program; Memorial Sloan-Kettering Cancer Center; New York, NY USA
| | - Michael Overholtzer
- Cell Biology Program; Memorial Sloan-Kettering Cancer Center; New York, NY USA
- BCMB Allied Program; Weill Cornell Medical College; New York, NY USA
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Nagashima LA, Akagi CY, Sano A, Álvares e Silva PL, Murata Y, Itano EN. Arthrographis kalrae soluble antigens present hemolytic and cytotoxic activities. Comp Immunol Microbiol Infect Dis 2014; 37:305-11. [PMID: 25449999 DOI: 10.1016/j.cimid.2014.09.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Revised: 09/01/2014] [Accepted: 09/26/2014] [Indexed: 10/24/2022]
Abstract
Arthrographis kalrae is a dimorphic, cosmopolitan and neurotropic fungus that has been described as a rare human pathogen. This study investigated the hemolytic and cytotoxic activities of A. kalrae cell-free antigens (CFAs). Total CFAs and their Sephadex chromatography fractions were tested on mouse erythrocytes for hemolysis and on the P3U1 cell line for cytotoxicity. Hemolytic and cytotoxic activities were detected in distinct molecular mass (MM) fractions. Additionally, antibodies against isogenic erythrocytes sensitized with CFAs (anti-E-CFAs) inhibited hemolysis but not cytotoxicity. Hemolysis was not affected by heating, and a higher reactivity was detected in the carbohydrate-rich fractions, which decreased after reduction by periodate treatment. The pioneering nature of this work is due to the demonstration of the cytotoxic activity in A. kalrae and the suggestion that this activity may be due to molecules distinct from the hemolytic factor, with the latter potentially being a component with a high MM.
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Affiliation(s)
- Luciene Airy Nagashima
- State University of Londrina, Rod. Celso Garcia Cid, km 380, 86057-970 Londrina, PR, Brazil
| | - Claudia Yuri Akagi
- State University of Londrina, Rod. Celso Garcia Cid, km 380, 86057-970 Londrina, PR, Brazil
| | - Ayako Sano
- University of the Ryukyus, Okinawa, Japan
| | | | | | - Eiko Nakagawa Itano
- State University of Londrina, Rod. Celso Garcia Cid, km 380, 86057-970 Londrina, PR, Brazil.
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Ferreira RM, Machado JC, Figueiredo C. Clinical relevance of Helicobacter pylori vacA and cagA genotypes in gastric carcinoma. Best Pract Res Clin Gastroenterol 2014; 28:1003-15. [PMID: 25439067 DOI: 10.1016/j.bpg.2014.09.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 08/21/2014] [Accepted: 09/15/2014] [Indexed: 02/08/2023]
Abstract
Helicobacter pylori infection is the major etiological factor of gastric carcinoma. This disease is the result of a long, multistep, and multifactorial process, which occurs only in a small proportion of patients infected with H. pylori. Gastric carcinoma development is influenced by host genetic susceptibility factors, environmental factors, and H. pylori virulence. H. pylori is genetically highly variable, and variability that affects H. pylori virulence factors may be useful to identify strains with different degrees of pathogenicity. This review will focus on VacA and CagA that have polymorphic regions that impact their functional properties. The characterization of H. pylori vacA and cagA-associated could be useful for identifying patients at highest risk of disease, who could be offered H. pylori eradication therapy and who could be included in programs of more intensive surveillance in an attempt to reduce gastric carcinoma incidence.
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Affiliation(s)
- Rui M Ferreira
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Portugal
| | - José C Machado
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Ceu Figueiredo
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine of the University of Porto, Porto, Portugal.
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Abstract
The discovery of Helicobacter pylori three decades ago is a modern medical success story. It markedly changed our understanding of the pathophysiology of gastroduodenal diseases and led to an improvement in the treatment of diseases related to H. pylori infection. Many of these diseases (such as ulcer disease and mucosal associated lymphoid tissue lymphoma) have become curable, and others (gastric cancer) might be preventable with the application of H. pylori eradication therapy. Since its discovery, H. pylori has also been identified as a trigger for some extragastric diseases. Promising results in this exciting field might have a clinical effect in the near future. This Timeline gives an overview of the success of clinical research on H. pylori to date and highlights some future trends in this area.
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Abstract
BACKGROUND Gastric cancer is the second most common cause of cancer deaths worldwide. The vast majority of gastric cancers are inflammation-related cancers caused by infection with Helicobacter pylori. H. pylori-induced oxidative stress damages DNA, resulting in genetic instability. In addition, H. pylori itself can cause DNA damage and epigenetic changes that trigger genetic instability and neoplastic transformation. SUMMARY H. pylori strain-specific components act in combination with host factors and environmental and dietary factors to greatly enhance the inflammatory response and thus the cancer risk. Variations in several key factors, such as the cag pathogenicity island and the VacA protein, can trigger a greater inflammatory response in host cells. Genetic polymorphisms in the host such as in the IL-1β gene, and chromosomes 9p21.3 and 10q23 also play a contributing role. Finally, diet is a major external factor that modulates the risk of gastric cancer. KEY MESSAGE The majority of gastric cancers are inflammation-related cancers caused by infection with H. pylori. Eradication of H. pylori is important for the prevention and treatment of gastric cancer. PRACTICAL IMPLICATIONS H. pylori eradication results in healing of gastritis and prevention of further H. pylori-induced genetic damage. Eradication of H. pylori prior to development of atrophic gastritis can prevent the development of gastric cancer. Japan has undertaken a nationwide program to identify and eliminate H. pylori, along with surveillance for those who underwent H. pylori eradication too late to eliminate cancer risk. Population-wide eradication of H. pylori will result in gastric cancer becoming a vanishingly rare disease.
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Affiliation(s)
- Wei Zhang
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Hong Lu
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - David Y. Graham
- Department of Medicine, Michael E. DeBakey VAMC and Baylor College of Medicine, Houston, Tex., USA
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Ki MR, Hwang M, Kim AY, Lee EM, Lee EJ, Lee MM, Sung SE, Kim SH, Lee HS, Jeong KS. Role of vacuolating cytotoxin VacA and cytotoxin-associated antigen CagA of Helicobacter pylori in the progression of gastric cancer. Mol Cell Biochem 2014; 396:23-32. [DOI: 10.1007/s11010-014-2138-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 06/17/2014] [Indexed: 12/28/2022]
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49
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Roesler BM, Rabelo-Gonçalves EMA, Zeitune JMR. Virulence Factors of Helicobacter pylori: A Review. CLINICAL MEDICINE INSIGHTS. GASTROENTEROLOGY 2014; 7:9-17. [PMID: 24833944 PMCID: PMC4019226 DOI: 10.4137/cgast.s13760] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 02/16/2014] [Accepted: 02/17/2014] [Indexed: 12/20/2022]
Abstract
Helicobacter pylori is a spiral-shaped Gram-negative bacterium that colonizes the human stomach and can establish a long-term infection of the gastric mucosa, a condition that affects the relative risk of developing various clinical disorders of the upper gastrointestinal tract, such as chronic gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma. H. pylori presents a high-level of genetic diversity, which can be an important factor in its adaptation to the host stomach and also for the clinical outcome of infection. There are important H. pylori virulence factors that, along with host characteristics and the external environment, have been associated with the different occurrences of diseases. This review is aimed to analyzing and summarizing the main of them and possible associations with the clinical outcome.
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Affiliation(s)
- Bruna M Roesler
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, Brazil. ; Center of Diagnosis of Digestive Diseases, Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, Brazil
| | - Elizabeth M A Rabelo-Gonçalves
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, Brazil. ; Center of Diagnosis of Digestive Diseases, Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, Brazil
| | - José M R Zeitune
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, Brazil. ; Center of Diagnosis of Digestive Diseases, Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, Brazil
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Mitchell HM, Rocha GA, Kaakoush NO, O’Rourke JL, Queiroz DMM. The Family Helicobacteraceae. THE PROKARYOTES 2014:337-392. [DOI: 10.1007/978-3-642-39044-9_275] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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