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1
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Turocy T, Crawford JM. Bacterial small molecule metabolites implicated in gastrointestinal cancer development. Nat Rev Microbiol 2025; 23:106-121. [PMID: 39375475 DOI: 10.1038/s41579-024-01103-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2024] [Indexed: 10/09/2024]
Abstract
Numerous associations have been identified between cancer and the composition and function of the human microbiome. As cancer remains the second leading global cause of mortality, investigating the carcinogenic contributions of microbiome members could advance our understanding of cancer risk and support potential therapeutic interventions. Although fluctuations in bacterial species have been associated with cancer progression, studying their small molecule metabolites offers one avenue to establish support for causal relationships and the molecular mechanisms governing host-microorganism interactions. In this Review, we explore the expanding repertoire of small molecule metabolites and their mechanisms implicated in the risk of developing gastrointestinal cancers.
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Affiliation(s)
- Tayah Turocy
- Department of Chemistry, Yale University, New Haven, CT, USA
- Institute of Biomolecular Design and Discovery, Yale University, West Haven, CT, USA
| | - Jason M Crawford
- Department of Chemistry, Yale University, New Haven, CT, USA.
- Institute of Biomolecular Design and Discovery, Yale University, West Haven, CT, USA.
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.
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2
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Wu H, Fujioka Y, Iwai N, Sakaguchi S, Suzuki Y, Nakano T. The relation in MreB and intrabacterial nanotransportation system for VacA in Helicobacter pylori. Med Mol Morphol 2024:10.1007/s00795-024-00416-w. [PMID: 39704844 DOI: 10.1007/s00795-024-00416-w] [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: 10/31/2024] [Accepted: 12/12/2024] [Indexed: 12/21/2024]
Abstract
Helicobacter pylori possesses an intrabacterial nanotransportation system (ibNoTS) for transporting VacA, CagA, and urease within the bacterial cytoplasm. This system is controlled by the extrabacterial environment. The transport routes of the system for VacA have not yet been studied in detail. In this study, we demonstrated by immunoelectron microscopy that VacA localizes closely with the MreB filament in the bacterium, and the MreB polymerization inhibitor A22 obstructs the transport of VacA by ibNoTS. These findings indicate that the route of ibNoTS for VacA is closely associated with the MreB filament Additionally, it was confirmed that VacA does not closely associate with the bacterial filament FtsZ, which is involved in the transport of the virulence factor urease, as previously suggested. We propose that the route of ibNoTS for VacA is associated with the MreB filament in H. pylori.
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Affiliation(s)
- Hong Wu
- Project Team for Study of Nanotransportation System, Center for Medical Research and Development, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan.
- Department of Microbiology and Infection Control, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan.
| | - Yoshihiko Fujioka
- Project Team for Study of Nanotransportation System, Center for Medical Research and Development, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan
- Department of Microbiology and Infection Control, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan
| | - Noritaka Iwai
- Project Team for Study of Nanotransportation System, Center for Medical Research and Development, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan
- Department of Life Science and Technology, Institute of Science Tokyo, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8501, Japan
| | - Shoichi Sakaguchi
- Department of Microbiology and Infection Control, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan
| | - Youichi Suzuki
- Department of Microbiology and Infection Control, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan
| | - Takashi Nakano
- Project Team for Study of Nanotransportation System, Center for Medical Research and Development, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan
- Department of Microbiology and Infection Control, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan
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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] [Download PDF] [Figures] [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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Wei BR, Zhao YJ, Cheng YF, Huang C, Zhang F. Helicobacter pylori infection and Parkinson's Disease: etiology, pathogenesis and levodopa bioavailability. Immun Ageing 2024; 21:1. [PMID: 38166953 PMCID: PMC10759355 DOI: 10.1186/s12979-023-00404-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 12/11/2023] [Indexed: 01/05/2024]
Abstract
Parkinson's disease (PD), a neurodegenerative disorder with an unknown etiology, is primarily characterized by the degeneration of dopamine (DA) neurons. The prevalence of PD has experienced a significant surge in recent years. The unidentified etiology poses limitations to the development of effective therapeutic interventions for this condition. Helicobacter pylori (H. pylori) infection has affected approximately half of the global population. Mounting evidences suggest that H. pylori infection plays an important role in PD through various mechanisms. The autotoxin produced by H. pylori induces pro-inflammatory cytokines release, thereby facilitating the occurrence of central inflammation that leads to neuronal damage. Simultaneously, H. pylori disrupts the equilibrium of gastrointestinal microbiota with an overgrowth of bacteria in the small intestinal known as small intestinal bacterial overgrowth (SIBO). This dysbiosis of the gut flora influences the central nervous system (CNS) through microbiome-gut-brain axis. Moreover, SIBO hampers levodopa absorption and affects its therapeutic efficacy in the treatment of PD. Also, H. pylori promotes the production of defensins to regulate the permeability of the blood-brain barrier, facilitating the entry of harmful factors into the CNS. In addition, H. pylori has been found to induce gastroparesis, resulting in a prolonged transit time for levodopa to reach the small intestine. H. pylori may exploit levodopa to facilitate its own growth and proliferation, or it can inflict damage to the gastrointestinal mucosa, leading to gastrointestinal ulcers and impeding levodopa absorption. Here, this review focused on the role of H. pylori infection in PD from etiology, pathogenesis to levodopa bioavailability.
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Affiliation(s)
- Bang-Rong Wei
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Centre, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yu-Jia Zhao
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Centre, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yu-Feng Cheng
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Centre, Zunyi Medical University, Zunyi, Guizhou, China
| | - Chun Huang
- The Fifth People's Hospital of Chongqing, Chongqing, China
| | - Feng Zhang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Centre, Zunyi Medical University, Zunyi, Guizhou, China.
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5
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Li R, Luo Y, Dong Q, Yin Y, Ma Y, Pan J, Pan Y, Zhang D. Association between the presence and genotype of Helicobacter pylori and periodontitis. Exp Ther Med 2023; 26:489. [PMID: 37753294 PMCID: PMC10518645 DOI: 10.3892/etm.2023.12188] [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: 02/15/2023] [Accepted: 08/09/2023] [Indexed: 09/28/2023] Open
Abstract
Whether Helicobacter pylori (H. pylori) infection is associated with periodontitis has been contested for decades. The relationship between H. pylori genotypes and periodontitis has not been clarified either. The present study provides a novel perspective to better understand the role of H. pylori in the pathogenesis of periodontitis. A total of 53 volunteers were recruited and divided into 3 groups in this cross-sectional study, namely the periodontally healthy group (15 participants), the stage I/II periodontitis group (20 participants) and the stage III/IV periodontitis group (18 participants). DNA from the subgingival plaque of all participants was extracted and PCR was performed using specific primers for the urease C gene and cytotoxin-associated gene A (cagA)/vacuolating cytotoxin gene A (vacA) to detect the presence and genotype of H. pylori. A χ2 test and one-way ANOVA were performed on the data. There was no significant difference in sex, age or body mass index between the groups. The detection rate of H. pylori was 39.62% in the total population and increased with the deepening of probing depth and clinical attachment loss. There were significant differences in the detection rate of H. pylori among the three groups, with 13.33, 40.00 and 61.11% in the periodontally healthy, stage I/II periodontitis and stage III/IV periodontitis groups, respectively (χ2=8.760, P<0.001). The cagA-/vacAs2m2 genotype was most commonly detected in the periodontally healthy group (100%). In the periodontitis group, cagA+/vacAs1m2 was the most commonly detected genotype in the stage I/II periodontitis group (37.5%) and cagA+/vacAs1m1 in the stage III/IV periodontitis group (36.3%). The results of the present study suggest that the detection rates and genotypes of H. pylori in the subgingival plaque are associated with the status of periodontitis. cagA+/vacAs1m1 and cagA+/vacAs1m2 may be considered virulence markers of periodontitis. However, given the small sample size and lack of correlation analysis of the study, further larger scale and high-quality clinical trials are required to confirm these findings.
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Affiliation(s)
- Rong Li
- Department of Periodontology, Shenzhen Stomatological Hospital, Southern Medical University, Shenzhen, Guangdong 518000, P.R. China
| | - Yuxiao Luo
- Department of Periodontology, School of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning 110002, P.R. China
| | - Qin Dong
- Department of Periodontology, School of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning 110002, P.R. China
| | - Yuqing Yin
- Department of Periodontology, School of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning 110002, P.R. China
| | - Yiwei Ma
- Department of Periodontology, School of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning 110002, P.R. China
| | - Jiayu Pan
- Department of Periodontology, Shenzhen Stomatological Hospital, Southern Medical University, Shenzhen, Guangdong 518000, P.R. China
| | - Yaping Pan
- Department of Periodontology, School of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning 110002, P.R. China
| | - Dongmei Zhang
- Department of Periodontics and Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning 110002, P.R. China
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6
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Wroblewski LE, Peek RM. Clinical Pathogenesis, Molecular Mechanisms of Gastric Cancer Development. Curr Top Microbiol Immunol 2023; 444:25-52. [PMID: 38231214 PMCID: PMC10924282 DOI: 10.1007/978-3-031-47331-9_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
The human pathogen Helicobacter pylori is the strongest known risk factor for gastric disease and cancer, and gastric cancer remains a leading cause of cancer-related death across the globe. Carcinogenic mechanisms associated with H. pylori are multifactorial and are driven by bacterial virulence constituents, host immune responses, environmental factors such as iron and salt, and the microbiota. Infection with strains that harbor the cytotoxin-associated genes (cag) pathogenicity island, which encodes a type IV secretion system (T4SS) confer increased risk for developing more severe gastric diseases. Other important H. pylori virulence factors that augment disease progression include vacuolating cytotoxin A (VacA), specifically type s1m1 vacA alleles, serine protease HtrA, and the outer-membrane adhesins HopQ, BabA, SabA and OipA. Additional risk factors for gastric cancer include dietary factors such as diets that are high in salt or low in iron, H. pylori-induced perturbations of the gastric microbiome, host genetic polymorphisms, and infection with Epstein-Barr virus. This chapter discusses in detail host factors and how H. pylori virulence factors augment the risk of developing gastric cancer in human patients as well as how the Mongolian gerbil model has been used to define mechanisms of H. pylori-induced inflammation and cancer.
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Affiliation(s)
- Lydia E Wroblewski
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Richard M Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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Torres J, Touati E. Mitochondrial Function in Health and Disease: Responses to Helicobacter pylori Metabolism and Impact in Gastric Cancer Development. Curr Top Microbiol Immunol 2023; 444:53-81. [PMID: 38231215 DOI: 10.1007/978-3-031-47331-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
Mitochondria are major cellular organelles that play an essential role in metabolism, stress response, immunity, and cell fate. Mitochondria are organized in a network with other cellular compartments, functioning as a signaling hub to maintain cells' health. Mitochondrial dysfunctions and genome alterations are associated with diseases including cancer. Mitochondria are a preferential target for pathogens, which have developed various mechanisms to hijack cellular functions for their benefit. Helicobacter pylori is recognized as the major risk factor for gastric cancer development. H. pylori induces oxidative stress and chronic gastric inflammation associated with mitochondrial dysfunction. Its pro-apoptotic cytotoxin VacA interacts with the mitochondrial inner membrane, leading to increased permeability and decreased ATP production. Furthermore, H. pylori induces mitochondrial DNA damage and mutation, concomitant with the development of gastric intraepithelial neoplasia as observed in infected mice. In this chapter, we present diverse aspects of the role of mitochondria as energy supplier and signaling hubs and their adaptation to stress conditions. The metabolic activity of mitochondria is directly linked to biosynthetic pathways. While H. pylori virulence factors and derived metabolites are essential for gastric colonization and niche adaptation, they may also impact mitochondrial function and metabolism, and may have consequences in gastric pathogenesis. Importantly, during its long way to reach the gastric epithelium, H. pylori faces various cellular types along the gastric mucosa. We discuss how the mitochondrial response of these different cells is affected by H. pylori and impacts the colonization and bacterium niche adaptation and point to areas that remain to be investigated.
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Affiliation(s)
- Javier Torres
- Unidad de Investigacion en Enfermedades Infecciosas, UMAE Pediatriıa, Instituto Mexicano del Seguro Social, Ciudad de Mexico, Mexico
| | - Eliette Touati
- Equipe DMic01-Infection, Génotoxicité et Cancer, Département de Microbiologie, UMR CNRS 6047, Institut Pasteur, Université Paris Cité, F-75015, Paris, France.
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8
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Tong Y, Gao H, Qi Q, Liu X, Li J, Gao J, Li P, Wang Y, Du L, Wang C. High fat diet, gut microbiome and gastrointestinal cancer. Theranostics 2021; 11:5889-5910. [PMID: 33897888 PMCID: PMC8058730 DOI: 10.7150/thno.56157] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/09/2021] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal cancer is currently one of the main causes of cancer death, with a large number of cases and a wide range of lesioned sites. A high fat diet, as a public health problem, has been shown to be correlated with various digestive system diseases and tumors, and can accelerate the occurrence of cancer due to inflammation and altered metabolism. The gut microbiome has been the focus of research in recent years, and associated with cell damage or tumor immune microenvironment changes via direct or extra-intestinal effects; this may facilitate the occurrence and development of gastrointestinal tumors. Based on research showing that both a high fat diet and gut microbes can promote the occurrence of gastrointestinal tumors, and that a high fat diet imbalances intestinal microbes, we propose that a high fat diet drives gastrointestinal tumors by changing the composition of intestinal microbes.
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Affiliation(s)
- Yao Tong
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Huiru Gao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Qiuchen Qi
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaoyan Liu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Juan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jie Gao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Peilong Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yunshan Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan, Shandong, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan, Shandong, China
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9
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Eisenbart SK, Alzheimer M, Pernitzsch SR, Dietrich S, Stahl S, Sharma CM. A Repeat-Associated Small RNA Controls the Major Virulence Factors of Helicobacter pylori. Mol Cell 2020; 80:210-226.e7. [PMID: 33002424 DOI: 10.1016/j.molcel.2020.09.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/29/2020] [Accepted: 09/04/2020] [Indexed: 12/12/2022]
Abstract
Many bacterial pathogens regulate their virulence genes via phase variation, whereby length-variable simple sequence repeats control the transcription or coding potential of those genes. Here, we have exploited this relationship between DNA structure and physiological function to discover a globally acting small RNA (sRNA) regulator of virulence in the gastric pathogen Helicobacter pylori. Our study reports the first sRNA whose expression is affected by a variable thymine (T) stretch in its promoter. We show the sRNA post-transcriptionally represses multiple major pathogenicity factors of H. pylori, including CagA and VacA, by base pairing to their mRNAs. We further demonstrate transcription of the sRNA is regulated by the nickel-responsive transcriptional regulator NikR (thus named NikS for nickel-regulated sRNA), thereby linking virulence factor regulation to nickel concentrations. Using in-vitro infection experiments, we demonstrate NikS affects host cell internalization and epithelial barrier disruption. Together, our results show NikS is a phase-variable, post-transcriptional global regulator of virulence properties in H. pylori.
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Affiliation(s)
- Sara K Eisenbart
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany
| | - Mona Alzheimer
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany
| | - Sandy R Pernitzsch
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany
| | - Sascha Dietrich
- Core Unit Systems Medicine, Interdisciplinary Center for Clinical Research (IZKF) of the University Hospital Würzburg, 97080 Würzburg, Germany
| | - Stephanie Stahl
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany
| | - Cynthia M Sharma
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany.
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10
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Functional Properties of Helicobacter pylori VacA Toxin m1 and m2 Variants. Infect Immun 2020; 88:IAI.00032-20. [PMID: 32284370 DOI: 10.1128/iai.00032-20] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/05/2020] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori colonizes the gastric mucosa and secretes a pore-forming toxin (VacA). Two main types of VacA, m1 and m2, can be distinguished by phylogenetic analysis. Type m1 forms of VacA have been extensively studied, but there has been relatively little study of m2 forms. In this study, we generated H. pylori strains producing chimeric proteins in which VacA m1 segments of a parental strain were replaced by corresponding m2 sequences. In comparison to the parental m1 VacA protein, a chimeric protein (designated m2/m1) containing m2 sequences in the N-terminal portion of the m region was less potent in causing vacuolation of HeLa cells, AGS gastric cells, and AZ-521 duodenal cells and had reduced capacity to cause membrane depolarization or death of AZ-521 cells. Consistent with the observed differences in activity, the chimeric m2/m1 VacA protein bound to cells at reduced levels compared to the binding levels of the parental m1 protein. The presence of two strain-specific insertions or deletions within or adjacent to the m region did not influence toxin activity. Experiments with human gastric organoids grown as monolayers indicated that m1 and m2/m1 forms of VacA had similar cell-vacuolating activities. Interestingly, both forms of VacA bound preferentially to the basolateral surface of organoid monolayers and caused increased cell vacuolation when interacting with the basolateral surface compared to the apical surface. These data provide insights into functional correlates of sequence variation in the VacA midregion (m region).
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11
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Sukhan DS, Vernygorodskyi SV, Haidukov NV, Ludkevich HP. Molecular and Genetic Aspects of Helicobacter pylori Interaction with Cells of Gastric Mucosa. CYTOL GENET+ 2020. [DOI: 10.3103/s0095452720020139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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12
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Abstract
Gastric environment has long been considered sterile, but the discovery of Helicobacter pylori (H. pylori) changed such concept in 1982. Over the past few decades, modern techniques have provided insight into microbial communities in the stomach and the interactions between communities, ranging from methods that rely on bacterial culture to the application of macrogenomics and high-throughput sequencing techniques. H. pylori is an important risk factor for gastric disease, but there may be other bacteria involved in the occurrence of gastric disease. This review summarizes the current progress in the understanding of the relationship between gastric microflora and gastric disease.
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Affiliation(s)
- Fang Liu
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, Key Laboratory of High Altitude Enviroesnment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang 712082, Shaanxi Province, China
| | - Tian Liang
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, Key Laboratory of High Altitude Enviroesnment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang 712082, Shaanxi Province, China
| | - Yan-Song Li
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, Key Laboratory of High Altitude Enviroesnment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang 712082, Shaanxi Province, China
| | - Su Bai
- Department of Digestive Medicine, Affiliated Hospital of Tibet University for Nationalities, Xianyang 712082, Shaanxi Province, China
| | - Long-Li Kang
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, Key Laboratory of High Altitude Enviroesnment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang 712082, Shaanxi Province, China
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13
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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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14
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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: 93] [Impact Index Per Article: 15.5] [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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15
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Shubin AV, Demidyuk IV, Komissarov AA, Rafieva LM, Kostrov SV. Cytoplasmic vacuolization in cell death and survival. Oncotarget 2018; 7:55863-55889. [PMID: 27331412 PMCID: PMC5342458 DOI: 10.18632/oncotarget.10150] [Citation(s) in RCA: 238] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 06/06/2016] [Indexed: 12/15/2022] Open
Abstract
Cytoplasmic vacuolization (also called cytoplasmic vacuolation) is a well-known morphological phenomenon observed in mammalian cells after exposure to bacterial or viral pathogens as well as to various natural and artificial low-molecular-weight compounds. Vacuolization often accompanies cell death; however, its role in cell death processes remains unclear. This can be attributed to studying vacuolization at the level of morphology for many years. At the same time, new data on the molecular mechanisms of the vacuole formation and structure have become available. In addition, numerous examples of the association between vacuolization and previously unknown cell death types have been reported. Here, we review these data to make a deeper insight into the role of cytoplasmic vacuolization in cell death and survival.
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Affiliation(s)
- Andrey V Shubin
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia.,Laboratory of Chemical Carcinogenesis, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.,Laboratory of Biologically Active Nanostructures, N.F. Gamaleya Institute of Epidemiology and Microbiology, Moscow, Russia
| | - Ilya V Demidyuk
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia
| | - Alexey A Komissarov
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia
| | - Lola M Rafieva
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia
| | - Sergey V Kostrov
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia
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16
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Chatre L, Fernandes J, Michel V, Fiette L, Avé P, Arena G, Jain U, Haas R, Wang TC, Ricchetti M, Touati E. Helicobacter pylori targets mitochondrial import and components of mitochondrial DNA replication machinery through an alternative VacA-dependent and a VacA-independent mechanisms. Sci Rep 2017; 7:15901. [PMID: 29162845 PMCID: PMC5698309 DOI: 10.1038/s41598-017-15567-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 10/30/2017] [Indexed: 12/31/2022] Open
Abstract
Targeting mitochondria is a powerful strategy for pathogens to subvert cell physiology and establish infection. Helicobacter pylori is a bacterial pathogen associated with gastric cancer development that is known to target mitochondria directly and exclusively through its pro-apoptotic and vacuolating cytotoxin VacA. By in vitro infection of gastric epithelial cells with wild-type and VacA-deficient H. pylori strains, treatment of cells with purified VacA proteins and infection of a mouse model, we show that H. pylori deregulates mitochondria by two novel mechanisms, both rather associated with host cell survival. First, early upon infection VacA induces transient increase of mitochondrial translocases and a dramatic accumulation of the mitochondrial DNA replication and maintenance factors POLG and TFAM. These events occur when VacA is not detected intracellularly, therefore do not require the direct interaction of the cytotoxin with the organelle, and are independent of the toxin vacuolating activity. In vivo, these alterations coincide with the evolution of gastric lesions towards severity. Second, H. pylori also induces VacA-independent alteration of mitochondrial replication and import components, suggesting the involvement of additional H. pylori activities in mitochondria-mediated effects. These data unveil two novel mitochondrial effectors in H. pylori-host interaction with links on gastric pathogenesis.
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Affiliation(s)
- Laurent Chatre
- Stem Cells and Development, Team Stability of Nuclear and Mitochondrial DNA, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France.,CNRS UMR3738, Paris, France
| | - Julien Fernandes
- Unit of Helicobacter Pathogenesis, Team Genotoxicity, Infection and Cancer, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France.,CNRS ERL3526, Paris, France.,UTechS PBI-CiTech, Institut Pasteur, Paris, 75015, France
| | - Valérie Michel
- Unit of Helicobacter Pathogenesis, Team Genotoxicity, Infection and Cancer, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France.,CNRS ERL3526, Paris, France
| | - Laurence Fiette
- Unit of Human Pathology and Animal Models, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France.,Paris Descartes University, PRES Sorbonne-Paris-Cité, Paris, France
| | - Patrick Avé
- Unit of Human Pathology and Animal Models, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France.,Paris Descartes University, PRES Sorbonne-Paris-Cité, Paris, France
| | - Giuseppe Arena
- Stem Cells and Development, Team Stability of Nuclear and Mitochondrial DNA, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France.,IRCM (Institut de Recherche en Cancérologie de Montpellier), Université de Montpellier, 34298, Montpellier, France.,INSERM U1194, Montpellier, France
| | - Utkarsh Jain
- Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, Ludwig-Maximilians-University, Pettenkoferstraße 9a, D-80336, Munich, Germany.,Amity Institute of Nanotechnology, Amity University, Sector 125, Noida, Uttar Pradesh, 201313, India
| | - Rainer Haas
- Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, Ludwig-Maximilians-University, Pettenkoferstraße 9a, D-80336, Munich, Germany.,German Center for Infection Research [DZIF], LMU, Munich, Germany
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, College of Physicians and Surgeons, Columbia University, New York, USA
| | - Miria Ricchetti
- Stem Cells and Development, Team Stability of Nuclear and Mitochondrial DNA, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France. .,CNRS UMR3738, Paris, France.
| | - Eliette Touati
- Unit of Helicobacter Pathogenesis, Team Genotoxicity, Infection and Cancer, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France. .,CNRS ERL3526, Paris, France.
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17
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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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18
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Link A, Langner C, Schirrmeister W, Habendorf W, Weigt J, Venerito M, Tammer I, Schlüter D, Schlaermann P, Meyer TF, Wex T, Malfertheiner P. Helicobacter pylori vacA genotype is a predominant determinant of immune response to Helicobacter pylori CagA. World J Gastroenterol 2017; 23:4712-4723. [PMID: 28765692 PMCID: PMC5514636 DOI: 10.3748/wjg.v23.i26.4712] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 04/05/2017] [Accepted: 05/19/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the frequency of Helicobacter pylori (H. pylori) CagA antibodies in H. pylori infected subjects and to identify potential histopathological and bacterial factors related to H. pylori CagA-immune response. METHODS Systematic data to H. pylori isolates, blood samples, gastric biopsies for histological and molecular analyses were available from 99 prospectively recruited subjects. Serological profile (anti-H. pylori, anti-CagA) was correlated with H. pylori isolates (cagA, EPIYA, vacA s/m genotype), histology (Sydney classification) and mucosal interleukin-8 (IL-8) mRNA and protein expression. Selected H. pylori strains were assessed for H. pylori CagA protein expression and IL-8 induction in co-cultivation model with AGS cells. RESULTS Thirty point three percent of microbiologically confirmed H. pylori infected patients were seropositive for CagA. Majority of H. pylori isolates were cagA gene positive (93.9%) with following vacA polymorphisms: 42.4% vacA s1m1, 23.2% s1m2 and 34.3% s2m2. Anti-CagA-IgG seropositivity was strongly associated with atrophic gastritis, increased mucosal inflammation according to the Sydney score, IL-8 and cagA mRNA expression. VacA s and m polymorphisms were the major determinants for positive (vacA s1m1) or negative (vacA s2m2) anti-CagA serological immune response, which also correlated with the in vitro inflammatory potential in AGS cells. In vitro co-cultivation of representative H. pylori strains with AGS cells confirmed functional CagA translocation, which showed only partial correlation with CagA seropositivity in patients, supporting vacA as major co-determinant of the immune response. CONCLUSION Serological immune response to H. pylori cagA+ strain in H. pylori infected patients is strongly associated with vacA polymorphism, suggesting the crucial role of bacterial factors in immune and clinical phenotype of the infection.
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19
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Fahimi F, Tohidkia MR, Fouladi M, Aghabeygi R, Samadi N, Omidi Y. Pleiotropic cytotoxicity of VacA toxin in host cells and its impact on immunotherapy. ACTA ACUST UNITED AC 2017; 7:59-71. [PMID: 28546954 PMCID: PMC5439391 DOI: 10.15171/bi.2017.08] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Revised: 02/09/2017] [Accepted: 02/13/2017] [Indexed: 12/17/2022]
Abstract
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Introduction: In the recent decades, a number of studies have highlighted the importance of Helicobacter pylori in the initiation and development of peptic ulcer and gastric cancer. Some potential virulence factors (e.g., urease, CagA, VacA, BabA) are exploited by this microorganism, facilitating its persistence through evading human defense mechanisms. Among these toxins and enzymes, vacuolating toxin A (VacA) is of a great importance in the pathogenesis of H. pylori. VacA toxin shows different pattern of cytotoxicity through binding to different cell surface receptors in various cells.
Methods: To highlight attempts in treatment for H. pylori infection, here, we discussed the VacA potential as a candidate for development of vaccine and targeted immunotherapy. Furthermore, we reviewed the related literature to provide key insights on association of the genetic variants of VacA with the toxicity of the toxin in cells.
Results: A number of investigations on the receptor(s) binding of VacA toxin confirmed the pleiotropic nature of VacA that uses a unique mechanism for internalization through some membrane components such as lipid rafts and glycophosphatidylinositol (GPI)-anchored proteins (GPI-AP). Considering the high potency of VacA toxin in the clinical presentations in infection and assisting persistence and colonization of H. pylori, it is considered as one of the pivotal components in production vaccines and monoclonal antibodies (mAbs).
Conclusion: It is possible to generate mAbs with a considerable potential to convert into secretory immunoglobulins that could penetrate into the niche of H. pylori and inhibit its normal functionalities. Further, conjugation of H. pylori targeting Ab fragments with the toxic agents or drug delivery systems (DDSs) offers new generation of H. pylori treatments.
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Affiliation(s)
- Farnaz Fahimi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Tohidkia
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Fouladi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Aghabeygi
- School of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Naser Samadi
- School of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yadollah Omidi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,School of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
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20
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Helicobacter pylori, Cancer, and the Gastric Microbiota. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 908:393-408. [PMID: 27573782 DOI: 10.1007/978-3-319-41388-4_19] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric adenocarcinoma is one of the leading causes of cancer-related death worldwide and Helicobacter pylori infection is the strongest known risk factor for this disease. Although the stomach was once thought to be a sterile environment, it is now known to house many bacterial species leading to a complex interplay between H. pylori and other residents of the gastric microbiota. In addition to the role of H. pylori virulence factors, host genetic polymorphisms, and diet, it is now becoming clear that components of the gastrointestinal microbiota may also influence H. pylori-induced pathogenesis. In this chapter, we discuss emerging data regarding the gastric microbiota in humans and animal models and alterations that occur to the composition of the gastric microbiota in the presence of H. pylori infection that may augment the risk of developing gastric cancer.
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21
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Valadan Tahbaz S, Yadegar A, Amirmozafari N, Yaghoobee S, Ehsani Ardakani MJ, Zojaji H. Occurrence of Helicobacter pylori and its major virulence genotypes in dental plaque samples of patients with chronic periodontitis in Iran. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2017; 10:S70-S78. [PMID: 29511475 PMCID: PMC5838184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
AIM This study was aimed to investigate the presence of H. pylori and its virulence genotypes in dental plaques of Iranian patients with chronic periodontitis. BACKGROUND Helicobacter pylori is a Gram-negative bacterium that is associated with atrophic gastritis, peptic ulcer, and gastric cancer. Several studies have detected this bacterium in the oral cavity, suggesting it as a potential reservoir. METHODS A hundred individuals were divided in 2 groups: 50 patients with chronic periodontitis (case group), and 50 subjects in non-periodontitis (control group). Supragingival and subgingival plaque samples were collected from the individuals using wood wedges and sterile paper points respectively, and prepared for PCR analysis. RESULTS Totally, H. pylori DNA was detected in 5 out of 100 (5%) dental plaques. Of 5 dental plaques positive for H. pylori, cagA gene was detected in 4 specimen, 3 in periodontitis group and one in non-periodontitis group. The H. pylori vacA s1m1 genotype was predominantly detected in 2/5 samples. The babA2 gene was detected in all (5/5) H. pylori-positive dental plaques. There was no significant correlation between the presence of H. pylori genotypes from dental plaques and chronic periodontitis (P > 0.05). CONCLUSION Our results revealed that the rate of H. pylori is very low in the dental plaques of Iranian patients with chronic periodontitis. Majority of H. pylori strains from oral cavity were highly virulent based on the main clinically virulence factors they carried.
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Affiliation(s)
- Sahel Valadan Tahbaz
- Department of Microbiology, Faculty of Basic Sciences, Research and Science Branch, Islamic Azad University, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nour Amirmozafari
- Microbiology Department, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Siamak Yaghoobee
- Department of Periodontics and Implant, Faculty of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Ehsani Ardakani
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Homayoun Zojaji
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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22
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Junaid M, Linn AK, Javadi MB, Al-Gubare S, Ali N, Katzenmeier G. Vacuolating cytotoxin A (VacA) - A multi-talented pore-forming toxin from Helicobacter pylori. Toxicon 2016; 118:27-35. [PMID: 27105670 DOI: 10.1016/j.toxicon.2016.04.037] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 03/12/2016] [Accepted: 04/18/2016] [Indexed: 12/18/2022]
Abstract
Helicobacter pylori is associated with severe and chronic diseases of the stomach and duodenum such as peptic ulcer, non-cardial adenocarcinoma and gastric lymphoma, making Helicobacter pylori the only bacterial pathogen which is known to cause cancer. The worldwide rate of incidence for these diseases is extremely high and it is estimated that about half of the world's population is infected with H. pylori. Among the bacterial virulence factors is the vacuolating cytotoxin A (VacA), which represents an important determinant of pathogenicity. Intensive characterization of VacA over the past years has provided insight into an ample variety of mechanisms contributing to host-pathogen interactions. The toxin is considered as an important target for ongoing research for several reasons: i) VacA displays unique features and structural properties and its mechanism of action is unrelated to any other known bacterial toxin; ii) the toxin is involved in disease progress and colonization by H. pylori of the stomach; iii) VacA is a potential and promising candidate for the inclusion as antigen in a vaccine directed against H. pylori and iv) the vacA gene is characterized by a high allelic diversity, and allelic variants contribute differently to the pathogenicity of H. pylori. Despite the accumulation of substantial data related to VacA over the past years, several aspects of VacA-related activity have been characterized only to a limited extent. The biologically most significant effect of VacA activity on host cells is the formation of membrane pores and the induction of vacuole formation. This review discusses recent findings and advances on structure-function relations of the H. pylori VacA toxin, in particular with a view to membrane channel formation, oligomerization, receptor binding and apoptosis.
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Affiliation(s)
- Muhammad Junaid
- Department of Pharmacy, Division of Pharmacology, University of Malakand, Khyber Pakhtunkhwa 18550, Pakistan; Bacterial Toxin Research Cluster, Institute of Molecular Biosciences, Mahidol University, Nakornpathom 73170, Thailand.
| | - Aung Khine Linn
- Bacterial Toxin Research Cluster, Institute of Molecular Biosciences, Mahidol University, Nakornpathom 73170, Thailand.
| | - Mohammad Bagher Javadi
- Bacterial Toxin Research Cluster, Institute of Molecular Biosciences, Mahidol University, Nakornpathom 73170, Thailand.
| | - Sarbast Al-Gubare
- Bacterial Toxin Research Cluster, Institute of Molecular Biosciences, Mahidol University, Nakornpathom 73170, Thailand.
| | - Niaz Ali
- Department of Basic Medical Sciences, Khyber Medical University, Peshawar 25000, Pakistan.
| | - Gerd Katzenmeier
- Bacterial Toxin Research Cluster, Institute of Molecular Biosciences, Mahidol University, Nakornpathom 73170, Thailand.
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23
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Interplay of the Gastric Pathogen Helicobacter pylori with Toll-Like Receptors. BIOMED RESEARCH INTERNATIONAL 2015; 2015:192420. [PMID: 25945326 PMCID: PMC4402485 DOI: 10.1155/2015/192420] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 12/29/2014] [Indexed: 12/18/2022]
Abstract
Toll-like receptors (TLRs) are crucial for pathogen recognition and downstream signaling to induce effective immunity. The gastric pathogen Helicobacter pylori is a paradigm of persistent bacterial infections and chronic inflammation in humans. The chronicity of inflammation during H. pylori infection is related to the manipulation of regulatory cytokines. In general, the early detection of H. pylori by TLRs and other pattern recognition receptors (PRRs) is believed to induce a regulatory cytokine or chemokine profile that eventually blocks the resolution of inflammation. H. pylori factors such as LPS, HSP-60, NapA, DNA, and RNA are reported in various studies to be recognized by specific TLRs. However, H. pylori flagellin evades the recognition of TLR5 by possessing a conserved N-terminal motif. Activation of TLRs and resulting signal transduction events lead to the production of pro- and anti-inflammatory mediators through activation of NF-κB, MAP kinases, and IRF signaling pathways. The genetic polymorphisms of these important PRRs are also implicated in the varied outcome and disease progression. Hence, the interplay of TLRs and bacterial factors highlight the complexity of innate immune recognition and immune evasion as well as regulated processes in the progression of associated pathologies. Here we will review this important aspect of H. pylori infection.
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24
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Yadegar A, Mobarez AM, Alebouyeh M, Mirzaei T, Kwok T, Zali MR. Clinical relevance of cagL gene and virulence genotypes with disease outcomes in a Helicobacter pylori infected population from Iran. World J Microbiol Biotechnol 2014; 30:2481-90. [PMID: 24854336 DOI: 10.1007/s11274-014-1673-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Accepted: 05/16/2014] [Indexed: 12/11/2022]
Abstract
Helicobacter pylori infection is common in Iran as in other developing countries. Certain genotypes of H. pylori have been associated with increased occurrence of chronic gastritis, peptic ulcers, and gastric adenocarcinoma. The aim of this study was to investigate the clinical relevance of cagL gene and other virulence genotypes of H. pylori isolates with clinical outcomes in Iranian patients. Totally, 126 symptomatic patients who underwent gastroduodenal endoscopy were enrolled in the study. Sixty-one H. pylori strains were isolated from the patients studied. The presence of the cagL, cagA, vacA, iceA, babA2 and sabA genes in the corresponding H. pylori isolates were determined by polymerase chain reaction and the results were compared with clinical outcomes and histopathology. The cagL, cagA, vacA s1, vacA s2, vacA m1, vacA m2, iceA1, iceA2, babA 2 , and sabA genotypes were detected in 96.7, 85.2, 75.4, 24.6, 29.5, 70.5, 42.6, 23, 96.7, and 83.6% of the isolates, respectively. The three genotypic combinations, cagL/cagA/vacAs1m1/iceA1/babA2/sabA, cagL/cagA/vacAs1m2/iceA1/babA2/sabA, and cagL/cagA/vacAs1m2/iceA2/babA2/sabA were determined as the most prevalent combined genotypes. There was a significant correlation between the presence of cagL gene and cagA positivity (P = 0.02). No significant correlation was found between the various genotypes and clinical outcomes (P > 0.05). The present study showed a very high prevalence of cagL genotype among the H. pylori isolates from Iranian patients. Our results demonstrated that neither single genotype nor combination genotypes of virulence-associated genes was significantly helpful markers for predicting the severity of gastroduodenal disease associated with H. pylori infection in Iranian patients.
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Affiliation(s)
- Abbas Yadegar
- Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Abreu MT, Peek RM. Gastrointestinal malignancy and the microbiome. Gastroenterology 2014; 146:1534-1546.e3. [PMID: 24406471 PMCID: PMC3995897 DOI: 10.1053/j.gastro.2014.01.001] [Citation(s) in RCA: 234] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 12/18/2013] [Accepted: 01/03/2014] [Indexed: 12/13/2022]
Abstract
Microbial species participate in the genesis of a substantial number of malignancies-in conservative estimates, at least 15% of all cancer cases are attributable to infectious agents. Little is known about the contribution of the gastrointestinal microbiome to the development of malignancies. Resident microbes can promote carcinogenesis by inducing inflammation, increasing cell proliferation, altering stem cell dynamics, and producing metabolites such as butyrate, which affect DNA integrity and immune regulation. Studies in human beings and rodent models of cancer have identified effector species and relationships among members of the microbial community in the stomach and colon that increase the risk for malignancy. Strategies to manipulate the microbiome, or the immune response to such bacteria, could be developed to prevent or treat certain gastrointestinal cancers.
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Affiliation(s)
- Maria T Abreu
- Division of Gastroenterology, Departments of Medicine and Microbiology and Immunology, University of Miami, Miami, Florida
| | - Richard M Peek
- Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University, Nashville, Tennessee.
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Wu H, Nakano T, Matsuzaki Y, Ooi Y, Kohno T, Ishihara S, Sano K. A new type of intrabacterial nanotransportation system for VacA in Helicobacter pylori. Med Mol Morphol 2014; 47:224-32. [PMID: 24420644 DOI: 10.1007/s00795-013-0068-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Accepted: 12/11/2013] [Indexed: 12/20/2022]
Abstract
Helicobacter pylori possesses intrabacterial nanotransportation systems (ibNoTSs) for CagA and urease. Both systems are UreI-dependent and urea-independent, and activated by extrabacterial acid. The activation occurs/appears within 15 min after exposure to extrabacterial acid stimulation. Although it has been clarified that VacA is secreted via the type-V secretion machinery, it remains unclear how this toxin is transported toward the machinery. To clarify the intrabacterial nanotransportation system for H. pylori VacA, immunoelectron microscopic analysis was performed in this study. VacA shifted to the periphery of the bacterial cytoplasm at 30 min after the extracellular pH change, whereas CagA and urease did so within 15 min. Studies using an ureI-deletion mutant revealed that unlike CagA and urease transport, VacA transport was not UreI-dependent. VacA secretion was accelerated without an increase in the production of VacA 30 min after the exposure to extrabacterial acid. These findings indicated that H. pylori possesses a novel type of ibNoTS for VacA, which is different from that for CagA or urease, in response time and dependency of UreI.
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Affiliation(s)
- Hong Wu
- Department of Microbiology and Infection Control, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan,
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Pachathundikandi SK, Tegtmeyer N, Backert S. Signal transduction of Helicobacter pylori during interaction with host cell protein receptors of epithelial and immune cells. Gut Microbes 2013; 4:454-74. [PMID: 24280762 PMCID: PMC3928158 DOI: 10.4161/gmic.27001] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Helicobacter pylori infections can induce pathologies ranging from chronic gastritis, peptic ulceration to gastric cancer. Bacterial isolates harbor numerous well-known adhesins, vacuolating cytotoxin VacA, protease HtrA, urease, peptidoglycan, and type IV secretion systems (T4SS). It appears that H. pylori targets more than 40 known host protein receptors on epithelial or immune cells. A series of T4SS components such as CagL, CagI, CagY, and CagA can bind to the integrin α 5β 1 receptor. Other targeted membrane-based receptors include the integrins αvβ 3, αvβ 5, and β 2 (CD18), RPTP-α/β, GP130, E-cadherin, fibronectin, laminin, CD46, CD74, ICAM1/LFA1, T-cell receptor, Toll-like receptors, and receptor tyrosine kinases EGFR, ErbB2, ErbB3, and c-Met. In addition, H. pylori is able to activate the intracellular receptors NOD1, NOD2, and NLRP3 with important roles in innate immunity. Here we review the interplay of various bacterial factors with host protein receptors. The contribution of these interactions to signal transduction and pathogenesis is discussed.
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28
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Tegtmeyer N, Rivas Traverso F, Rohde M, Oyarzabal OA, Lehn N, Schneider-Brachert W, Ferrero RL, Fox JG, Berg DE, Backert S. Electron microscopic, genetic and protein expression analyses of Helicobacter acinonychis strains from a Bengal tiger. PLoS One 2013; 8:e71220. [PMID: 23940723 PMCID: PMC3733902 DOI: 10.1371/journal.pone.0071220] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 06/26/2013] [Indexed: 12/21/2022] Open
Abstract
Colonization by Helicobacter species is commonly noted in many mammals. These infections often remain unrecognized, but can cause severe health complications or more subtle host immune perturbations. The aim of this study was to isolate and characterize putative novel Helicobacter spp. from Bengal tigers in Thailand. Morphological investigation (Gram-staining and electron microscopy) and genetic studies (16SrRNA, 23SrRNA, flagellin, urease and prophage gene analyses, RAPD DNA fingerprinting and restriction fragment polymorphisms) as well as Western blotting were used to characterize the isolated Helicobacters. Electron microscopy revealed spiral-shaped bacteria, which varied in length (2.5-6 µm) and contained up to four monopolar sheathed flagella. The 16SrRNA, 23SrRNA, sequencing and protein expression analyses identified novel H. acinonychis isolates closely related to H. pylori. These Asian isolates are genetically very similar to H. acinonychis strains of other big cats (cheetahs, lions, lion-tiger hybrid and other tigers) from North America and Europe, which is remarkable in the context of the great genetic diversity among worldwide H. pylori strains. We also found by immunoblotting that the Bengal tiger isolates express UreaseA/B, flagellin, BabA adhesin, neutrophil-activating protein NapA, HtrA protease, γ-glutamyl-transpeptidase GGT, Slt lytic transglycosylase and two DNA transfer relaxase orthologs that were known from H. pylori, but not the cag pathogenicity island, nor CagA, VacA, SabA, DupA or OipA proteins. These results give fresh insights into H. acinonychis genetics and the expression of potential pathogenicity-associated factors and their possible pathophysiological relevance in related gastric infections.
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MESH Headings
- Animals
- Bacterial Proteins/analysis
- DNA Fingerprinting
- Gene Expression Profiling
- Gene Expression Regulation, Bacterial
- Genes, Bacterial
- Helicobacter/genetics
- Helicobacter/isolation & purification
- Helicobacter/ultrastructure
- Helicobacter Infections/microbiology
- Helicobacter Infections/veterinary
- Microscopy, Electron
- RNA, Ribosomal, 16S/analysis
- RNA, Ribosomal, 16S/genetics
- RNA, Ribosomal, 23S/analysis
- RNA, Ribosomal, 23S/genetics
- Random Amplified Polymorphic DNA Technique
- Tigers/microbiology
- Urease/genetics
- Urease/metabolism
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Affiliation(s)
- Nicole Tegtmeyer
- Institute of Medical Microbiology, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | | | - Manfred Rohde
- Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Omar A. Oyarzabal
- Institute for Environmental Health, Inc., Seattle, Washington, United States of America
| | - Norbert Lehn
- Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany
| | - Wulf Schneider-Brachert
- Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany
| | - Richard L. Ferrero
- Centre for Innate Immunity & Infectious Diseases, Monash Institute of Medical Research, Clayton, Australia
| | - James G. Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Douglas E. Berg
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Steffen Backert
- Institute of Medical Microbiology, Otto von Guericke University Magdeburg, Magdeburg, Germany
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Abstract
Half of the world's population is infected with Helicobacter pylori and approximately 20% of infected individuals develop overt clinical disease such as ulcers and stomach cancer. Paradoxically, despite its classification as a class I carcinogen, H. pylori has been shown to be protective against development of asthma, allergy, and esophageal disease. Given these conflicting roles for H. pylori, researchers are attempting to define the environmental, host, and pathogen interactions that ultimately result in severe disease in some individuals. From the bacterial perspective, the toxins, CagA and VacA, have each been shown to be polymorphic and to contribute to disease in an allele-dependent manner. Based on the notable advances that have recently been made in the CagA field, herein we review recent studies that have begun to shed light on the role of CagA polymorphism in H. pylori disease. Moreover, we discuss the potential interaction of CagA and VacA as a mediator of gastric disease.
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30
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Wroblewski LE, Peek RM. When guests simply will not leave. Cell Host Microbe 2012; 12:733-4. [PMID: 23245316 DOI: 10.1016/j.chom.2012.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Chronic pathogens have evolved exquisite mechanisms of self-regulation via manipulation of host signaling pathways; however, pathologic consequences may ensue. Tsugawa et al. (2012) now report a mechanism of checks and balances used by Helicobacter pylori that is undermined by gastric stem cells, which may lower the threshold for gastric cancer.
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Affiliation(s)
- Lydia E Wroblewski
- Department of Medicine, Vanderbilt University, Nashville, TN 37232-2279, USA
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Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori. Cell Commun Signal 2011; 9:28. [PMID: 22044679 PMCID: PMC3266215 DOI: 10.1186/1478-811x-9-28] [Citation(s) in RCA: 128] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2011] [Accepted: 11/01/2011] [Indexed: 02/08/2023] Open
Abstract
Helicobacter pylori is a highly successful pathogen uniquely adapted to colonize humans. Gastric infections with this bacterium can induce pathology ranging from chronic gastritis and peptic ulcers to gastric cancer. More virulent H. pylori isolates harbour numerous well-known adhesins (BabA/B, SabA, AlpA/B, OipA and HopZ) and the cag (cytotoxin-associated genes) pathogenicity island encoding a type IV secretion system (T4SS). The adhesins establish tight bacterial contact with host target cells and the T4SS represents a needle-like pilus device for the delivery of effector proteins into host target cells such as CagA. BabA and SabA bind to blood group antigen and sialylated proteins respectively, and a series of T4SS components including CagI, CagL, CagY and CagA have been shown to target the integrin β1 receptor followed by injection of CagA across the host cell membrane. The interaction of CagA with membrane-anchored phosphatidylserine may also play a role in the delivery process. While substantial progress has been made in our current understanding of many of the above factors, the host cell receptors for OipA, HopZ and AlpA/B during infection are still unknown. Here we review the recent progress in characterizing the interactions of the various adhesins and structural T4SS proteins with host cell factors. The contribution of these interactions to H. pylori colonization and pathogenesis is discussed.
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