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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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2
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Mukherjee S, Patra R, Behzadi P, Masotti A, Paolini A, Sarshar M. Toll-like receptor-guided therapeutic intervention of human cancers: molecular and immunological perspectives. Front Immunol 2023; 14:1244345. [PMID: 37822929 PMCID: PMC10562563 DOI: 10.3389/fimmu.2023.1244345] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 09/07/2023] [Indexed: 10/13/2023] Open
Abstract
Toll-like receptors (TLRs) serve as the body's first line of defense, recognizing both pathogen-expressed molecules and host-derived molecules released from damaged or dying cells. The wide distribution of different cell types, ranging from epithelial to immune cells, highlights the crucial roles of TLRs in linking innate and adaptive immunity. Upon stimulation, TLRs binding mediates the expression of several adapter proteins and downstream kinases, that lead to the induction of several other signaling molecules such as key pro-inflammatory mediators. Indeed, extraordinary progress in immunobiological research has suggested that TLRs could represent promising targets for the therapeutic intervention of inflammation-associated diseases, autoimmune diseases, microbial infections as well as human cancers. So far, for the prevention and possible treatment of inflammatory diseases, various TLR antagonists/inhibitors have shown to be efficacious at several stages from pre-clinical evaluation to clinical trials. Therefore, the fascinating role of TLRs in modulating the human immune responses at innate as well as adaptive levels directed the scientists to opt for these immune sensor proteins as suitable targets for developing chemotherapeutics and immunotherapeutics against cancer. Hitherto, several TLR-targeting small molecules (e.g., Pam3CSK4, Poly (I:C), Poly (A:U)), chemical compounds, phytocompounds (e.g., Curcumin), peptides, and antibodies have been found to confer protection against several types of cancers. However, administration of inappropriate doses of such TLR-modulating therapeutics or a wrong infusion administration is reported to induce detrimental outcomes. This review summarizes the current findings on the molecular and structural biology of TLRs and gives an overview of the potency and promises of TLR-directed therapeutic strategies against cancers by discussing the findings from established and pipeline discoveries.
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Affiliation(s)
- Suprabhat Mukherjee
- Integrative Biochemistry & Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India
| | - Ritwik Patra
- Integrative Biochemistry & Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India
| | - Payam Behzadi
- Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran
| | - Andrea Masotti
- Research Laboratories, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Alessandro Paolini
- Research Laboratories, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Meysam Sarshar
- Research Laboratories, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
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Dawson RE, Deswaerte V, West AC, Sun E, Wray‐McCann G, Livis T, Kumar B, Rodriguez E, Gabay C, Ferrero RL, Jenkins BJ. The cytosolic DNA sensor AIM2 promotes Helicobacter-induced gastric pathology via the inflammasome. Immunol Cell Biol 2023; 101:444-457. [PMID: 36967659 PMCID: PMC10952813 DOI: 10.1111/imcb.12641] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 02/14/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023]
Abstract
Helicobacter pylori (H. pylori) infection can trigger chronic gastric inflammation perpetuated by overactivation of the innate immune system, leading to a cascade of precancerous lesions culminating in gastric cancer. However, key regulators of innate immunity that promote H. pylori-induced gastric pathology remain ill-defined. The innate immune cytosolic DNA sensor absent in melanoma 2 (AIM2) contributes to the pathogenesis of numerous autoimmune and chronic inflammatory diseases, as well as cancers including gastric cancer. We therefore investigated whether AIM2 contributed to the pathogenesis of Helicobacter-induced gastric disease. Here, we reveal that AIM2 messenger RNA and protein expression levels are elevated in H. pylori-positive versus H. pylori-negative human gastric biopsies. Similarly, chronic Helicobacter felis infection in wild-type mice augmented Aim2 gene expression levels compared with uninfected controls. Notably, gastric inflammation and hyperplasia were less severe in H. felis-infected Aim2-/- versus wild-type mice, evidenced by reductions in gastric immune cell infiltrates, mucosal thickness and proinflammatory cytokine and chemokine release. In addition, H. felis-driven proliferation and apoptosis in both gastric epithelial and immune cells were largely attenuated in Aim2-/- stomachs. These observations in Aim2-/- mouse stomachs correlated with decreased levels of inflammasome activity (caspase-1 cleavage) and the mature inflammasome effector cytokine, interleukin-1β. Taken together, this work uncovers a pathogenic role for the AIM2 inflammasome in Helicobacter-induced gastric disease, and furthers our understanding of the host immune response to a common pathogen and the complex and varying roles of AIM2 at different stages of cancerous and precancerous gastric disease.
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Affiliation(s)
- Ruby E Dawson
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health SciencesMonash UniversityClaytonVICAustralia
| | - Virginie Deswaerte
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health SciencesMonash UniversityClaytonVICAustralia
| | - Alison C West
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health SciencesMonash UniversityClaytonVICAustralia
| | - Ekimei Sun
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health SciencesMonash UniversityClaytonVICAustralia
| | - Georgie Wray‐McCann
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health SciencesMonash UniversityClaytonVICAustralia
| | - Thaleia Livis
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health SciencesMonash UniversityClaytonVICAustralia
| | - Beena Kumar
- Department of Anatomical PathologyMonash HealthClaytonVICAustralia
| | - Emiliana Rodriguez
- Pathology and Immunology DepartmentCMU/University of GenevaGenevaSwitzerland
| | - Cem Gabay
- Pathology and Immunology DepartmentCMU/University of GenevaGenevaSwitzerland
| | - Richard L Ferrero
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health SciencesMonash UniversityClaytonVICAustralia
- Department of Microbiology, Biomedicine Discovery InstituteMonash UniversityClaytonVICAustralia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health SciencesMonash UniversityClaytonVICAustralia
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Bai H, Kawahara M, Takahashi M. Identification of menaquinone-4 (vitamin K2) target genes in bovine endometrial epithelial cells in vitro. Theriogenology 2023; 198:183-193. [PMID: 36592516 DOI: 10.1016/j.theriogenology.2022.12.033] [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: 10/22/2022] [Revised: 12/22/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022]
Abstract
The effect of vitamin K on bovine endometrial epithelial cells has not been thoroughly investigated. The objective of this study was to examine the effect of the biologically active form of vitamin K, menaquinone-4, on gene expression in bovine endometrial epithelial cells. First, we examined the mRNA and protein expression levels of UBIAD1, a menaquinone-4 biosynthetic enzyme. Second, we screened for potential target genes of menaquinone-4 in bovine endometrial epithelial cells using RNA-sequencing. We found 50 differentially expressed genes; 42 were upregulated, and 8 were downregulated. Among them, a dose-dependent response to menaquinone-4 was observed for the top three upregulated (TRIB3, IL6, and TNFAIP3) and downregulated (CDC6, ORC1, and RRM2) genes. It has been suggested that these genes play important roles in reproductive events. In addition, GDF15 and VEGFA, which are important for cellular functions as they are commonly involved in pathways, such as positive regulation of cell communication, cell differentiation, and positive regulation of MAPK cascade, were upregulated in endometrial epithelial cells by menaquinone-4 treatment. To the best of our knowledge, this is the first study showing the expression of UBIAD1 in the bovine uterus. Moreover, the study determined menaquinone-4 target genes in bovine endometrial epithelial cells, which may positively affect pregnancy with alteration of gene expression in cattle uterus.
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Affiliation(s)
- Hanako Bai
- Laboratory of Animal Breeding and Reproduction, Research Faculty of Agriculture, Hokkaido University, Kita-ku Kita 9 Nishi 9, Sapporo, 060-8589, Japan.
| | - Manabu Kawahara
- Laboratory of Animal Breeding and Reproduction, Research Faculty of Agriculture, Hokkaido University, Kita-ku Kita 9 Nishi 9, Sapporo, 060-8589, Japan.
| | - Masashi Takahashi
- Laboratory of Animal Breeding and Reproduction, Research Faculty of Agriculture, Hokkaido University, Kita-ku Kita 9 Nishi 9, Sapporo, 060-8589, Japan; Global Station for Food, Land and Water Resources, Global Institution for Collaborative Research and Education, Hokkaido University, Kita-ku Kita 9 Nishi 9, Sapporo, 060-0815, Japan.
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The functions and molecular mechanisms of Tribbles homolog 3 (TRIB3) implicated in the pathophysiology of cancer. Int Immunopharmacol 2023; 114:109581. [PMID: 36527874 DOI: 10.1016/j.intimp.2022.109581] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/21/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022]
Abstract
Currently, cancer ranks as the second leading cause of death worldwide, and at the same time, the burden of cancer continues to increase. The underlying molecular pathways involved in the initiation and development of cancer are the subject of considerable research worldwide. Further understanding of these pathways may lead to new cancer treatments. Growing data suggest that Tribble's homolog 3 (TRIB3) is essential in oncogenesis in many types of cancer. The mammalian tribbles family's proteins regulate various cellular and physiological functions, such as the cell cycle, stress response, signal transduction, propagation, development, differentiation, immunity, inflammatory processes, and metabolism. To exert their activities, Tribbles proteins must alter key signaling pathways, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/AKT pathways. Recent evidence supports that TRIB3 dysregulation has been linked to various diseases, including tumor development and chemoresistance. It has been speculated that TRIB3 may either promote or inhibit the onset and development of cancer. However, it is still unclear how TRIB3 performs this dual function in cancer. In this review, we present and discuss the most recent data on the role of TRIB3 in cancer pathophysiology and chemoresistance. Furthermore, we describe in detail the molecular mechanism TRIB3 regulates in cancer.
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Zabrodskaya Y, Plotnikova M, Gavrilova N, Lozhkov A, Klotchenko S, Kiselev A, Burdakov V, Ramsay E, Purvinsh L, Egorova M, Vysochinskaya V, Baranovskaya I, Brodskaya A, Povalikhin R, Vasin A. Exosomes Released by Influenza-Virus-Infected Cells Carry Factors Capable of Suppressing Immune Defense Genes in Naïve Cells. Viruses 2022; 14:2690. [PMID: 36560694 PMCID: PMC9781497 DOI: 10.3390/v14122690] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/23/2022] [Accepted: 11/29/2022] [Indexed: 12/05/2022] Open
Abstract
Background: Exosomes are involved in intercellular communication and can transfer regulatory molecules between cells. Consequently, they can participate in host immune response regulation. For the influenza A virus (IAV), there is very limited information on changes in exosome composition during cell infection shedding light on the potential role of these extracellular membrane vesicles. Thus, the aim of our work was to study changes in exosomal composition following IAV infection of cells, as well as to evaluate their effect on uninfected cells. Methods: To characterize changes in the composition of cellular miRNAs and mRNAs of exosomes during IAV infection of A549 cells, NGS was used, as well as PCR to identify viral genes. Naïve A549 cells were stimulated with infected-cell-secreted exosomes for studying their activity. Changes in the expression of genes associated with the cell's immune response were shown using PCR. The effect of exosomes on IAV replication was shown in MDCK cells using In-Cell ELISA and PCR of the supernatants. Results: A change in the miRNA composition (miR-21-3p, miR-26a-5p, miR-23a-5p, miR-548c-5p) and mRNA composition (RPL13A, MKNK2, TRIB3) of exosomes under the influence of the IAV was shown. Many RNAs were involved in the regulation of the immune response of the cell, mainly by suppressing it. After exosome stimulation of naïve cells, a significant decrease in the expression of genes involved in the immune response was shown (RIG1, IFIT1, MDA5, COX2, NFκB, AnxA1, PKR, IL6, IL18). When infecting MDCK cells, a significant decrease in nucleoprotein levels was observed in the presence of exosomes secreted by mock-infected cells. Viral levels in supernatants also decreased. Conclusions: Exosomes secreted by IAV-infected cells could reduce the immune response of neighboring intact cells, leading to more effective IAV replication. This may be associated both with regulatory functions of cellular miRNAs and mRNAs carried by exosomes, or with the presence of viral mRNAs encoding proteins with an immunosuppressive function.
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Affiliation(s)
- Yana Zabrodskaya
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia
- Smorodintsev Research Institute of Influenza, 15/17 Ulitsa Professora Popova, 197376 St. Petersburg, Russia
| | - Marina Plotnikova
- Smorodintsev Research Institute of Influenza, 15/17 Ulitsa Professora Popova, 197376 St. Petersburg, Russia
| | - Nina Gavrilova
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia
- Smorodintsev Research Institute of Influenza, 15/17 Ulitsa Professora Popova, 197376 St. Petersburg, Russia
| | - Alexey Lozhkov
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia
- Smorodintsev Research Institute of Influenza, 15/17 Ulitsa Professora Popova, 197376 St. Petersburg, Russia
| | - Sergey Klotchenko
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia
- Smorodintsev Research Institute of Influenza, 15/17 Ulitsa Professora Popova, 197376 St. Petersburg, Russia
| | - Artem Kiselev
- Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, 775 Woodlot Dr, East Lansing, MI 48824, USA
| | - Vladimir Burdakov
- Petersburg Nuclear Physics Institute Named by B. P. Konstantinov of National Research Center, Kurchatov Institute, 1 mkr. Orlova roshcha, 188300 Gatchina, Russia
| | - Edward Ramsay
- Saint Petersburg Pasteur Institute, 14 Ulitsa Mira, 197101 St. Petersburg, Russia
| | - Lada Purvinsh
- Biology Science Department, The University of Chicago, 947 E. 58th St., Chicago, IL 60637, USA
| | - Marja Egorova
- Smorodintsev Research Institute of Influenza, 15/17 Ulitsa Professora Popova, 197376 St. Petersburg, Russia
| | - Vera Vysochinskaya
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia
- Smorodintsev Research Institute of Influenza, 15/17 Ulitsa Professora Popova, 197376 St. Petersburg, Russia
| | - Irina Baranovskaya
- Smorodintsev Research Institute of Influenza, 15/17 Ulitsa Professora Popova, 197376 St. Petersburg, Russia
- Department of Physiology, Augusta University, 1462 Laney Walker Blvd, CA-3149, Augusta, GA 30912, USA
| | - Alexandra Brodskaya
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia
- Smorodintsev Research Institute of Influenza, 15/17 Ulitsa Professora Popova, 197376 St. Petersburg, Russia
| | - Roman Povalikhin
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia
| | - Andrey Vasin
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia
- Smorodintsev Research Institute of Influenza, 15/17 Ulitsa Professora Popova, 197376 St. Petersburg, Russia
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Helicobacter pylori Pathogen-Associated Molecular Patterns: Friends or Foes? Int J Mol Sci 2022; 23:ijms23073531. [PMID: 35408892 PMCID: PMC8998707 DOI: 10.3390/ijms23073531] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 03/18/2022] [Accepted: 03/21/2022] [Indexed: 01/08/2023] Open
Abstract
Microbial infections are sensed by the host immune system by recognizing signature molecules called Pathogen-Associated Molecular Patterns—PAMPs. The binding of these biomolecules to innate immune receptors, called Pattern Recognition Receptors (PRRs), alerts the host cell, activating microbicidal and pro-inflammatory responses. The outcome of the inflammatory cascade depends on the subtle balance between the bacterial burn and the host immune response. The role of PRRs is to promote the clearance of the pathogen and to limit the infection by bumping inflammatory response. However, many bacteria, including Helicobacter pylori, evolved to escape PRRs’ recognition through different camouflages in their molecular pattern. This review examines all the different types of H. pylori PAMPs, their roles during the infection, and the mechanisms they evolved to escape the host recognition.
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Rawson A, Saxena V, Gao H, Hooks J, Xuei X, McGuire P, Hato T, Hains DS, Anderson RM, Schwaderer AL. A Pilot Single Cell Analysis of the Zebrafish Embryo Cellular Responses to Uropathogenic Escherichia coli Infection. Pathog Immun 2022; 7:1-18. [PMID: 35178490 PMCID: PMC8843076 DOI: 10.20411/pai.v7i1.479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/06/2021] [Indexed: 11/23/2022] Open
Abstract
Background: Uropathogenic Escherichia coli (UPEC) infections are common and when they disseminate can be of high morbidity.
Methods: We studied the effects of UPEC infection using single cell RNA sequencing (scRNAseq) in zebrafish. Bulk RNA sequencing has historically been used to evaluate gene expression patterns, but scRNAseq allows gene expression to be evaluated at the single cell level and is optimal for evaluating heterogeneity within cell types and rare cell types. Zebrafish cohorts were injected with either saline or UPEC,and scRNAseq and canonical pathway analyses were performed.
Results: Canonical pathway analysis of scRNAseq data provided key information regarding innate immune pathways in the cells determined to be thymus cells, ionocytes, macrophages/monocytes, and pronephros cells. Pathways activated in thymus cells included interleukin 6 (IL-6) signaling and production of reactive oxygen species. Fc receptor-mediated phagocytosis was a leading canonical pathway in the pronephros and macrophages. Genes that were downregulated in UPEC vs saline exposed embryos involved the cellular response to the Gram-negative endotoxin lipopolysaccharide (LPS) and included Forkhead Box O1a (Foxo1a), Tribbles Pseudokinase 3 (Trib3), Arginase 2 (Arg2) and Polo Like Kinase 3 (Plk3).
Conclusions: Because 4-day post fertilization zebrafish embryos only have innate immune systems, the scRNAseq provides insights into pathways and genes that cell types utilize in the bacterial response. Based on our analysis, we have identified genes and pathways that might serve as genetic targets for treatment and further investigation in UPEC infections at the single cell level.
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Affiliation(s)
- Ashley Rawson
- Indiana University School of Medicine, Department of Pediatrics, Division of Nephrology
| | - Vijay Saxena
- Indiana University School of Medicine, Department of Pediatrics, Division of Nephrology
| | - Hongyu Gao
- Indiana University School of Medicine, Department of Medical & Molecular Genetics
| | - Jenaya Hooks
- Indiana University School of Medicine, Department of Pediatrics, Division of Nephrology
| | - Xiaoling Xuei
- Indiana University School of Medicine, Department of Medical & Molecular Genetics
| | - Patrick McGuire
- Indiana University School of Medicine, Department of Medical & Molecular Genetics
| | - Takashi Hato
- Indiana University School of Medicine, Department of Medicine, Division of Nephrology
| | - David S. Hains
- Indiana University School of Medicine, Department of Pediatrics, Division of Nephrology
| | - Ryan M. Anderson
- University of Chicago, Section of Endocrinology, Diabetes and Metabolism
- CORRESPONDING AUTHOR Andrew Schwaderer, Indiana University School of Medicine, Riley Hospital for Children, 699 Riley Hospital Dr., RR230, Indianapolis, IN 46202; Phone: 317-274-2527;
| | - Andrew L. Schwaderer
- Indiana University School of Medicine, Department of Pediatrics, Division of Nephrology
- CORRESPONDING AUTHOR Ryan M Anderson, University of Chicago, Medicine-Endocrinology, Chicago, IL 60637;
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Shang S, Yang YW, Chen F, Yu L, Shen SH, Li K, Cui B, Lv XX, Zhang C, Yang C, Liu J, Yu JJ, Zhang XW, Li PP, Zhu ST, Zhang HZ, Hua F. TRIB3 reduces CD8 + T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer. Sci Transl Med 2022; 14:eabf0992. [PMID: 34985967 DOI: 10.1126/scitranslmed.abf0992] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Shuang Shang
- Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Yu-Wei Yang
- Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Fei Chen
- Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Liang Yu
- Department of Colorectal Surgery, State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Shuo-Hao Shen
- Department of Colorectal Surgery, State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Ke Li
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Bing Cui
- Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Xiao-Xi Lv
- Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Cheng Zhang
- Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Chen Yang
- Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Jing Liu
- Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Jiao-Jiao Yu
- Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Xiao-Wei Zhang
- Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Ping-Ping Li
- Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Sheng-Tao Zhu
- Beijing Digestive Diseases Center, Beijing Friendship Hospital, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing 100050, P.R. China
| | - Hai-Zeng Zhang
- Department of Colorectal Surgery, State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Fang Hua
- Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
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10
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Liu L, Liu B, Yu J, Zhang D, Shi J, Liang P. Development of a Toll-Like Receptor-Based Gene Signature That Can Predict Prognosis, Tumor Microenvironment, and Chemotherapy Response for Hepatocellular Carcinoma. Front Mol Biosci 2021; 8:729789. [PMID: 34621787 PMCID: PMC8490642 DOI: 10.3389/fmolb.2021.729789] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/16/2021] [Indexed: 11/19/2022] Open
Abstract
Objective: Emerging evidence highlights the implications of the toll-like receptor (TLR) signaling pathway in the pathogenesis and therapeutic regimens of hepatocellular carcinoma (HCC). Herein, a prognostic TLR-based gene signature was conducted for HCC. Methods: HCC-specific TLRs were screened in the TCGA cohort. A LASSO model was constructed based on prognosis-related HCC-specific TLRs. The predictive efficacy, sensitivity, and independency of this signature was then evaluated and externally verified in the ICGC, GSE14520, and GSE76427 cohorts. The associations between this signature and tumor microenvironment (stromal/immune score, immune checkpoint expression, and immune cell infiltrations) and chemotherapy response were assessed in HCC specimens. The expression of TLRs in this signature was verified in HCC and normal liver tissues by Western blot. Following si-MAP2K2 transfection, colony formation and apoptosis of Huh7 and HepG2 cells were examined. Results: Herein, we identified 60 HCC-specific TLRs. A TLR-based gene signature (MAP2K2, IRAK1, RAC1, TRAF3, MAP3K7, and SPP1) was conducted for HCC prognosis. High-risk patients exhibited undesirable outcomes. ROC curves confirmed the well prediction performance of this signature. Multivariate Cox regression analysis demonstrated that the signature was an independent prognostic indicator. Also, high-risk HCC was characterized by an increased immune score, immune checkpoint expression, and immune cell infiltration. Meanwhile, high-risk patients displayed higher sensitivity to gemcitabine and cisplatin. The dysregulation of TLRs in the signature was confirmed in HCC. MAP2K2 knockdown weakened colony formation and elevated apoptosis of Huh7 and HepG2 cells. Conclusion: Collectively, this TLR-based gene signature might assist clinicians to select personalized therapy programs for HCC patients.
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Affiliation(s)
- Lixia Liu
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.,Department of Ultrasound, Affiliated Hospital of Hebei University, Baoding, China
| | - Bin Liu
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Institute of Life Science and Green Development, Hebei University, Baoding, China
| | - Jie Yu
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China
| | - Dongyun Zhang
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China
| | - Jianhong Shi
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Institute of Life Science and Green Development, Hebei University, Baoding, China
| | - Ping Liang
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China
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11
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Herrera-Pariente C, Capó-García R, Díaz-Gay M, Carballal S, Muñoz J, Llach J, Sánchez A, Bonjoch L, Arnau-Collell C, Soares de Lima Y, Golubicki M, Jung G, Lozano JJ, Castells A, Balaguer F, Bujanda L, Castellví-Bel S, Moreira L. Identification of New Genes Involved in Germline Predisposition to Early-Onset Gastric Cancer. Int J Mol Sci 2021; 22:1310. [PMID: 33525650 PMCID: PMC7866206 DOI: 10.3390/ijms22031310] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 12/24/2022] Open
Abstract
The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC patients without previous germline mutation identified. WES was also performed in nine tumor samples to analyze the somatic profile using SigProfilerExtractor tool. Sequencing germline data were filtered to select those variants with plausible pathogenicity, rare frequency and previously involved in cancer. Then, a manual filtering was performed to prioritize genes according to current knowledge and function. These genetic variants were prevalidated with Integrative Genomics Viewer 2.8.2 (IGV). Subsequently, a further selection step was carried out according to function and information obtained from tumor samples. After IGV and selection step, 58 genetic variants in 52 different candidate genes were validated by Sanger sequencing. Among them, APC, FAT4, CTNND1 and TLR2 seem to be the most promising genes because of their role in hereditary cancer syndromes, tumor suppression, cell adhesion and Helicobacter pylori recognition, respectively. These encouraging results represent the open door to the identification of new genes involved in GC germline predisposition.
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Affiliation(s)
- Cristina Herrera-Pariente
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Roser Capó-García
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Marcos Díaz-Gay
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Sabela Carballal
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Jenifer Muñoz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Joan Llach
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Ariadna Sánchez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Laia Bonjoch
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Coral Arnau-Collell
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Yasmin Soares de Lima
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Mariano Golubicki
- Oncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, C1264 Buenos Aires, Argentina;
- Molecular Biology Laboratory, Hospital of Gastroenterology “Dr. C. B. Udaondo”, C1264 Buenos Aires, Argentina
| | - Gerhard Jung
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Juan José Lozano
- Bioinformatics Platform, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, 08036 Barcelona, Spain;
| | - Antoni Castells
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Francesc Balaguer
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Luis Bujanda
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Biodonostia Health Research Institute, Basque Country University (UPV/EHU), 20014 San Sebastián, Spain;
| | - Sergi Castellví-Bel
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
| | - Leticia Moreira
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (C.H.-P.); (R.C.-G.); (M.D.-G.); (S.C.); (J.M.); (J.L.); (A.S.); (L.B.); (C.A.-C.); (Y.S.d.L.); (G.J.); (A.C.); (F.B.)
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12
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FitzGerald R, Devapal M, Hickey JJ, McNamara D, Kelleher D, Smith SM. Purification of Total RNA from Stomach Tissue Biopsies. Methods Mol Biol 2021; 2283:51-59. [PMID: 33765309 DOI: 10.1007/978-1-0716-1302-3_7] [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: 06/12/2023]
Abstract
In order to further our understanding of the physiological consequences of Helicobacter pylori infection , analysis of clinical tissue specimens is required. To this end, RNA is frequently isolated from stomach biopsies of H. pylori-infected patients and compared to samples from uninfected controls to monitor gene expression using molecular methods such as reverse-transcription real-time PCR, microarrays, and next-generation sequencing. The successful purification of sufficient quantities of high-quality RNA is essential for accurate and reproducible downstream analysis. This chapter describes the key steps for high-quality RNA purification from human tissue samples, including sample collection and storage, tissue disruption and lysis, RNA purification, and assessment of RNA yield and quality.
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Affiliation(s)
| | - Malini Devapal
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - John J Hickey
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland
| | | | - Dermot Kelleher
- Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Sinéad M Smith
- Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
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13
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Fukase K. Glycoconjugates for Adjuvants and Self-Adjuvanting Vaccines. COMPREHENSIVE GLYCOSCIENCE 2021:166-184. [DOI: 10.1016/b978-0-12-819475-1.00099-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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14
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Abstract
Helicobacter pylori (H. pylori) represents one of the most widespread bacterial infections globally. Infection causes chronic gastritis and increases the risk of peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. The pioneering discovery of H. pylori by Marshall and Warren in the early 1980s has initiated fervent research into H. pylori as a pathogen ever since. This chapter aims to provide an overview of our understanding of H. pylori infection and its management, with a focus on current options for diagnosis, the challenges associated with H. pylori eradication, and the need for alternative therapeutic strategies based on furthering our understanding of host: H. pylori interactions.
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Affiliation(s)
| | - Sinéad M Smith
- Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
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15
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Robinson K, Atherton JC. The Spectrum of Helicobacter-Mediated Diseases. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2020; 16:123-144. [PMID: 33197219 DOI: 10.1146/annurev-pathol-032520-024949] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Helicobacter pylori is the leading cause of peptic ulcer disease. The infection has been implicated in more than 75% of duodenal ulcer cases and 17% of gastric ulcer cases. H. pylori has been classified as a human carcinogen, since it is the main cause of distal gastric adenocarcinoma and B cell mucosa-associated lymphoid tissue lymphoma. Evidence also links H. pylori with extragastric conditions including iron deficiency anemia, idiopathic thrombocytopenic purpura, and vitamin B12 deficiency. Studies indicate that H. pylori may be protective against other conditions of the gastrointestinal tract (e.g., reflux esophagitis and related pathologies) and elsewhere in the body (e.g., asthma). The infection is asymptomatic in the vast majority of cases; more serious outcomes occur in only 10-15% of infected individuals. Despite extensive research over the past 3 decades, there is no effective vaccine, and the circumstances leading to disease development remain unclear. In addition, there is now a growing prevalence of antimicrobial resistance in H. pylori. This review discusses these important issues.
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Affiliation(s)
- Karen Robinson
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, United Kingdom.,Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2RD United Kingdom;
| | - John C Atherton
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, United Kingdom.,Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2RD United Kingdom;
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16
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Zhang F, Liu X, Huo B, Li B, Zhang R. Mechanism Analysis of Coix Seed in Gastric Cancer Treatment Based on Biological Network Modules. Nat Prod Commun 2020. [DOI: 10.1177/1934578x20927521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Coix seed, the mature seed of Coix lacryma-jobi L., is a traditional herb widely used in various cancer adjuvant treatments; however, its mechanism is unknown. The aim of this study was to reveal the multitarget mechanisms of Coix seed in the treatment of gastric cancer (GC) by biological network and modular analysis methods. Forty-one ingredients and 482 targets of Coix seed and 165 GC-related genes were obtained from databases. Twelve on-target genes ( AICDA, CASP3, EP300, ERBB2, FGFR2, IL12A, IL12B, IL1B, LOX, TJP1, TP53, and TRIB3) of Coix seed overlapped with GC-related genes. Using compound-target and protein–protein interaction network analyses, we discovered the core targets of Coix seed. Markov cluster algorithm-based modular analysis identified 5 potential module targets of Coix seed for GC. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated the vast actions of Coix seed, which involve pathways in cancer, the cell cycle, receptor signal transduction, deoxyribonucleic acid damage response, transcriptional regulation, apoptosis, and cell connections. This study elucidated the potential mechanisms of Coix seed on GC, which may lead to the development of an effective drug. Additionally, this study showed the feasibility of network and modular analysis methods to investigate traditional Chinese medicinal herbal mechanisms and may provide a new angle for further research in the field of anticancer mechanisms and multitarget drugs.
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Affiliation(s)
- Fengbin Zhang
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaoyan Liu
- Department of TCM Pediatric, TCM Hospital of Hebei Province, Shijiazhuang, China
| | - Bingjie Huo
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Bing Li
- Institute of Information on Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ruixing Zhang
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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17
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Jeffrey MP, MacPherson CW, Mathieu O, Tompkins TA, Green-Johnson JM. Secretome-Mediated Interactions with Intestinal Epithelial Cells: A Role for Secretome Components from Lactobacillus rhamnosus R0011 in the Attenuation of Salmonella enterica Serovar Typhimurium Secretome and TNF-α-Induced Proinflammatory Responses. THE JOURNAL OF IMMUNOLOGY 2020; 204:2523-2534. [PMID: 32238458 DOI: 10.4049/jimmunol.1901440] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 02/26/2020] [Indexed: 12/13/2022]
Abstract
Recent evidence suggests that lactic acid bacteria communicate with host cells via secretome components to influence immune responses but less is known about gut-pathogen secretomes, impact of lactic acid bacteria secretomes on host-pathogen interactions, and the mechanisms underlying these interactions. Genome-wide microarrays and cytokine profiling were used to interrogate the impact of the Lactobacillus rhamnosus R0011 secretome (LrS) on TNF-α and Salmonella enterica subsp. enterica serovar Typhimurium secretome (STS)-induced outcomes in human intestinal epithelial cells. The LrS attenuated both TNF-α- and STS-induced gene expression involved in NF-κB and MAPK activation, as well as expression of genes involved in other immune-related signaling pathways. Specifically, the LrS induced the expression of dual specificity phosphatase 1 (DUSP1), activating transcription factor 3 (ATF3), and tribbles pseudokinase 3 (TRIB3), negative regulators of innate immune signaling, in HT-29 intestinal epithelial cells challenged with TNF-α or STS. TNF-α- and STS-induced acetylation of H3 and H4 histones was attenuated by the LrS, as was the production of TNF-α- and STS-induced proinflammatory cytokines and chemokines. Interestingly, the LrS induced production of macrophage migration inhibitory factor (MIF), a cytokine involved in host-microbe interactions at the gut interface. We propose that the LrS attenuates proinflammatory mediator expression through increased transcription of negative regulators of innate immune activity and changes in global H3 and H4 histone acetylation. To our knowledge, these findings provide novel insights into the complex multifaceted mechanisms of action behind secretome-mediated interdomain communication at the gut-mucosal interface.
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Affiliation(s)
- Michael P Jeffrey
- Applied Bioscience Graduate Program and the Faculty of Science, Ontario Technical University, Oshawa, Ontario L1G 0C5, Canada; and
| | - Chad W MacPherson
- Rosell Institute for Microbiome and Probiotics, Montreal, Quebec H4P 2R2, Canada
| | - Olivier Mathieu
- Rosell Institute for Microbiome and Probiotics, Montreal, Quebec H4P 2R2, Canada
| | - Thomas A Tompkins
- Rosell Institute for Microbiome and Probiotics, Montreal, Quebec H4P 2R2, Canada
| | - Julia M Green-Johnson
- Applied Bioscience Graduate Program and the Faculty of Science, Ontario Technical University, Oshawa, Ontario L1G 0C5, Canada; and
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18
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Eed EM, Hawash YA, Khalifa AS, Alsharif KF, Alghamdi SA, Almalki AA, Almehmadi MM, Ismail KA, Taha AA, Saber T. Association of toll-like receptors 2, 4, 9 and 10 genes polymorphisms and Helicobacter pylori-related gastric diseases in Saudi patients. Indian J Med Microbiol 2020; 38:94-100. [PMID: 32719215 DOI: 10.4103/ijmm.ijmm_20_164] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Purpose Helicobacter pylori is one of the most prevalent human pathogens worldwide. However, the outcomes of H. pylori infection are markedly variable from asymptomatic mild lesion to malignant transformation. Many factors are suggested to influence these infection outcomes, including host immunity and genetic susceptibility. Toll-like receptors (TLRs) can recognise different microbial components and play an essential role in the mucosal immune response against H. pylori infection. Materials and Methods The association between the common single nucleotide polymorphisms (SNPs) in the genes of TLR2, 4, 9 and 10 and H. pylori-related gastric diseases were investigated by molecular methods after the confirmation of H. pylori infection. The study included 210 patients in three groups; chronic gastritis (n = 90), peptic ulcer disease (PUD) (n = 75) and gastric carcinoma (n = 45). Results The results showed a significant association between TLR4 SNPs (rs 4986790 and rs 4986791) and the presence of H. pylori infection, especially in chronic gastritis patient group. Furthermore, TLR9-rs352140 TT genotype was more prevalent among chronic gastritis patient group. TLR10-rs 10004195 TT genotype was found to be less prevalent among H. pylori-related chronic gastritis and PUD and was suspected to have a protective effect. TLR2 SNPs (rs3804099 and rs3804100) showed no significant statistical difference between H. pylori-infected patients and the controls. Conclusion TLR genes polymorphisms may play a role in H. pylori infection susceptibility and may influence its outcomes; however, the ethnic and other factors may modify this effect.
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Affiliation(s)
- Emad M Eed
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia; Department of Medical Microbiology and Immunology, Faculty of Medicine, Menoufia University, Menoufia, Cairo, Egypt
| | - Yousry A Hawash
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia; Department of Molecular and Clinical Parasitology, National Liver Institute, Menoufia University, Menoufia, Cairo, Egypt
| | - Amany S Khalifa
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Taif University, Taif, Saudi Arabia; Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Cairo, Egypt
| | - Khalaf F Alsharif
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Saleh A Alghamdi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Abdulraheem A Almalki
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Mazen M Almehmadi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Khadiga A Ismail
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia; Department of Parasitology, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
| | - Azza A Taha
- Department of Public Health and Community Medicine, Faculty of Medicine, Menoufia University, Menoufia, Cairo, Egypt
| | - Taisir Saber
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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19
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Swanson GM, Estill M, Diamond MP, Legro RS, Coutifaris C, Barnhart KT, Huang H, Hansen KR, Trussell JC, Coward RM, Zhang H, Goodrich R, Krawetz SA. Human chromatin remodeler cofactor, RNA interactor, eraser and writer sperm RNAs responding to obesity. Epigenetics 2020; 15:32-46. [PMID: 31354029 PMCID: PMC6961666 DOI: 10.1080/15592294.2019.1644880] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 07/05/2019] [Accepted: 07/09/2019] [Indexed: 12/23/2022] Open
Abstract
In the United States almost 33% of adults are considered obese (BMI > 30 kg/m2). Both animal models and to a lesser extent human studies, have associated BMI, a measure of obesity, with alterations in sperm DNA methylation and RNAs. Sperm RNAs from the Assessment of Multiple Gestations from Ovarian Stimulation trial, were isolated and sequenced. A Generalized Linear Model identified 487 BMI associated human sperm RNA elements (short exon-sized sequences). They partitioned into four patterns; a continual increase with BMI, increase once obese (BMI>30 kg/m2); a steady decrease with BMI; and decrease once overweight (BMI 25 - 30 kg/m2). Gene Ontology revealed a unique relationship between BMI and transcripts associated with chromosome organization, adipogenesis, cellular stress and obesity-related inflammation. Coregulatory networks linked by Chromatin remodeler cofactors, RNA interactors, Erasers and Writers (CREWs) were uncovered to reveal a hierarchical epigenetic response pathway.
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Affiliation(s)
- Grace M. Swanson
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, USA
| | - Molly Estill
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, USA
| | - Michael P. Diamond
- Department of Obstetrics and Gynecology, Augusta University, Augusta, USA
| | - Richard S. Legro
- Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey, USA
| | - Christos Coutifaris
- Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, USA
| | - Kurt T. Barnhart
- Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, USA
| | - Hao Huang
- Department of Biostatistics, Yale University School of Public Health, New Haven, USA
| | - Karl R. Hansen
- Department of Obstetrics and Gynecology, University of Oklahoma College of Medicine, Oklahoma City, USA
| | - J. C. Trussell
- Urology Department, Upstate Medical University, Syracuse, USA
| | - R. Matthew Coward
- Department of Urology, University of North Carolina School of Medicine, Chapel Hill, USA
| | - Heping Zhang
- Department of Biostatistics, Yale University School of Public Health, New Haven, USA
| | - Robert Goodrich
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, USA
| | - Stephen A. Krawetz
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, USA
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20
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Clyne M, Rowland M. The Role of Host Genetic Polymorphisms in Helicobacter pylori Mediated Disease Outcome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:151-172. [PMID: 31016623 DOI: 10.1007/5584_2019_364] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The clinical outcome of infection with the chronic gastric pathogen Helicobacter pylori is not the same for all individuals and also differs in different ethnic groups. Infection occurs in early life (<3 years of age), and while all infected persons mount an immune response and develop gastritis, the majority of individuals are asymptomatic. However, up to 10-15% develop duodenal ulceration, up to 1% develop gastric cancer (GC) and up to 0.1% can develop gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The initial immune response fails to clear infection and H. pylori can persist for decades. H. pylori has been classified as a group one carcinogen by the WHO. Interestingly, development of duodenal ulceration protects against GC. Factors that determine the outcome of infection include the genotype of the infecting strains and the environment. Host genetic polymorphisms have also been identified as factors that play a role in mediating the clinical outcome of infection. Several studies present compelling evidence that polymorphisms in genes involved in the immune response such as pro and anti-inflammatory cytokines and pathogen recognition receptors (PRRs) play a role in modulating disease outcome. However, as the number of studies grows emerging confounding factors are small sample size and lack of appropriate controls, lack of consideration of environmental and bacterial factors and ethnicity of the population. This chapter is a review of current evidence that host genetic polymorphisms play a role in mediating persistent H. pylori infection and the consequences of the subsequent inflammatory response.
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Affiliation(s)
- Marguerite Clyne
- School of Medicine and The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
| | - Marion Rowland
- School of Medicine, University College Dublin, Dublin, Ireland
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21
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Gupta N, Maurya S, Verma H, Verma VK. Unraveling the factors and mechanism involved in persistence: Host-pathogen interactions in Helicobacter pylori. J Cell Biochem 2019; 120:18572-18587. [PMID: 31237031 DOI: 10.1002/jcb.29201] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Accepted: 05/20/2019] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori and humans have one of the most complex relationships in nature. How a bacterium manages to live in one of the harshest and hostile environments is a topic of unraveling mysteries. H. pylori is a prevalent species and it colonizes the human gut of more than 50% of the world population. It infects the epithelial region of antrum and persists there for a long period. Over the time of evolution, H. pylori has developed complex strategies to extend the degree of inflammation in gastric mucosa. H. pylori needs specific adaptations for initial colonization into the host environment like helical shape, flagellar movement, chemotaxis, and the production of urease enzyme that neutralizes acidic environment of the stomach. There are several factors from the bacterium as well as from the host that participate in these complex interactions. On the other hand, to establish the persistent infection, H. pylori escapes the immune system by mimicking the host antigens. This pathogen has the ability to dodge the immune system and then persist there in the form of host cell, which leads to immune tolerance. H. pylori has an ability to manipulate its own pathogen-associated molecular patterns, which leads to an inhibition in the binding with specific pattern recognition receptors of the host to avoid immune cell detection. Also, it manipulates the host metabolic homeostasis in the gastric epithelium. Besides, it has several genes, which may get involved in the acquisition of nutrition from the host to survive longer in the host. Due to the persistence of H. pylori, it causes chronic inflammation and raises the chances of gastric cancer. This review highlights the important elements, which are certainly responsible for the persistence of H. pylori in the human host.
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Affiliation(s)
- Nidhi Gupta
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Kishangarh, India
| | - Shweta Maurya
- Department of Microbiology, School of Life Sciences, Central University of Rajasthan, Kishangarh, India
| | - Harshvardhan Verma
- Department of Microbiology, School of Life Sciences, Central University of Rajasthan, Kishangarh, India
| | - Vijay K Verma
- Department of Microbiology, School of Life Sciences, Central University of Rajasthan, Kishangarh, India
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22
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The Relationship between Toll-like Receptors and Helicobacter pylori-Related Gastropathies: Still a Controversial Topic. J Immunol Res 2019; 2019:8197048. [PMID: 30863783 PMCID: PMC6378784 DOI: 10.1155/2019/8197048] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 01/02/2019] [Indexed: 12/13/2022] Open
Abstract
Innate immunity represents the first barrier against bacterial invasion. Toll-like receptors (TLRs) belong to the large family of pattern recognition receptors (PRRs), and their activation leads to the induction of inflammatory cytokines, chemokines, antigen-presenting molecules, and costimulatory molecules. Recent studies have focused on identifying the association between TLRs and Helicobacter pylori- (H. pylori-) related diseases. Therefore, this minireview focuses on assessing the role of these TLRs in the development of H. pylori-related gastropathies. Both TLR2 and TLR were found to be involved in H. pylori LPS recognition, with contradictory results most likely due to both the inability to obtain pure LPS in experimental studies and the heterogeneity of the bacterial LPS. In addition, TLR2 was found to be the most extensively expressed gene among all the TLRs in gastric tumors. High levels of TLR4 were also associated with a higher risk of gastric cancer. TLR5 was initially associated with the recognition of H. pylori flagellin, but it seems that this bacterium has developed mechanisms to escape this recognition representing an important factor involved in the persistence of this infection and subsequent carcinogenesis. TLR9, the only TLR with both anti- and proinflammatory roles, was involved in the recognition of H. pylori DNA. The dichotomous role of TLR9, promoting or suppressing the infection, depends on the gastric environment. Recently, TLR7 and TLR8 were shown to recognize purified H. pylori RNA, thereby inducing proinflammatory cytokines. TLR1 and TLR10 gene polymorphisms were associated with a higher risk for gastric cancer in H. pylori-infected individuals. Different gene polymorphisms of these TLRs were found to be associated with gastric cancer depending mostly on ethnicity. Further studies are required in order to develop preventive and therapeutic strategies against H. pylori infections based on the functions of TLRs.
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23
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Nagashima H, Yamaoka Y. Importance of Toll-like Receptors in Pro-inflammatory and Anti-inflammatory Responses by Helicobacter pylori Infection. Curr Top Microbiol Immunol 2019; 421:139-158. [PMID: 31123888 DOI: 10.1007/978-3-030-15138-6_6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Infectious diseases have been paramount among the threats to human health and survival throughout evolutionary history. Bacterial cell-surface molecules are key factors in the microorganism-host crosstalk, as they can interact with host pattern-recognition receptors (PRRs) of the gastrointestinal mucosa. The best-studied PRRs are toll-like receptors (TLRs). Because TLRs play an important key role in host defense, they have received increasing interest in the evolutionary and population genetics literature, and their variation represents a potential target of adaptive evolution. Helicobacter pylori is one of the commensal bacteria in our body and can have pathogenic properties in a subset of infected people. The history of H. pylori research indicated that humans and bacteria co-evolved during evolution. A genome-wide association study (GWAS) has opened the way for investigating the genomic evolution of bacterial pathogens during the colonization and infection of humans. Recent GWAS research emphasized the importance of TLRs, especially TLR10 during pathogenesis in H. pylori infection. We demonstrated that TLR10, whose ligand was unknown for a long time, can recognize H. pylori LPS. Our results of H. pylori research suggest that TLR10 might play an important role to also recognize other commensal bacteria. In this review, we discuss the importance of TLRs in pro-inflammatory and anti-inflammatory responses by H. pylori infection. Especially, we highlight the TLR10 interaction with H. pylori infection, providing new insights about TLR10 signaling.
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Affiliation(s)
- Hiroyuki Nagashima
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan.,Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita, 879-5593, Japan
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita, 879-5593, Japan. .,Department of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA.
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24
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Xu L, Gong C, Li G, Wei J, Wang T, Meng W, Shi M, Wang Y. Ebselen suppresses inflammation induced by Helicobacter pylori lipopolysaccharide via the p38 mitogen-activated protein kinase signaling pathway. Mol Med Rep 2018; 17:6847-6851. [PMID: 29488609 DOI: 10.3892/mmr.2018.8641] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 02/23/2017] [Indexed: 11/05/2022] Open
Abstract
Ebselen is a seleno-organic compound that has been demonstrated to have antioxidant and anti-inflammatory properties. A previous study determined that ebselen inhibits airway inflammation induced by inhalational lipopolysaccharide (LPS), however, the underlying molecular mechanism remains to be elucidated. The present study investigated the effect of ebselen on the glutathione peroxidase (GPX)‑reactive oxygen species (ROS) pathway and interleukin‑8 (IL‑8) expression induced by Helicobacter pylori LPS in gastric cancer (GC) cells. Cells were treated with 200 ng/ml H. pylori‑LPS in the presence or absence of ebselen for various durations and concentrations (µmol/l). The expression of toll‑like receptor 4 (TLR4), GPX2, GPX4, p38 mitogen‑activated protein kinase (p38 MAPK), phosphorylated‑p38 MAPK, ROS production and IL‑8 expression were detected with western blotting or ELISA. The present study revealed that TLR4 expression was upregulated; however, GPX2 and GPX4 expression was reduced following treatment with H. pylori LPS, which led to increased ROS production, subsequently altering the IL‑8 expression level in GC cells. Additionally, it was determined that ebselen prevented the reduction in GPX2/4 levels induced by H. pylori LPS, however, TLR4 expression was not affected. Ebselen may also block the expression of IL‑8 by inhibiting phosphorylation of p38 MAPK. These data suggest ebselen may inhibit ROS production triggered by H. pylori LPS treatment via GPX2/4 instead of TLR4 signaling and reduce phosphorylation of p38 MAPK, resulting in altered production of IL‑8. Ebselen may, therefore, be a potential therapeutic agent to mediate H. pylori LPS-induced cell damage.
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Affiliation(s)
- Ling Xu
- Department of Gastroenterology, Shanghai Tongren Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China
| | - Changguo Gong
- Department of Gastroenterology, Shanghai Tongren Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China
| | - Guangming Li
- Department of Gastroenterology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Jue Wei
- Department of Gastroenterology, Shanghai Tongren Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China
| | - Ting Wang
- Department of Gastroenterology, Shanghai Tongren Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China
| | - Wenying Meng
- Department of Gastroenterology, Shanghai Tongren Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China
| | - Min Shi
- Department of Gastroenterology, Shanghai Tongren Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China
| | - Yugang Wang
- Department of Gastroenterology, Shanghai Tongren Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China
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25
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Liu Y, Wang WM, Zou LY, Li L, Feng L, Pan MZ, Lv MY, Cao Y, Wang H, Kung HF, Pang JX, Fu WM, Zhang JF. Ubiquitin specific peptidase 5 mediates Histidine-rich protein Hpn induced cell apoptosis in hepatocellular carcinoma through P14-P53 signaling. Proteomics 2017; 17. [PMID: 28523650 DOI: 10.1002/pmic.201600350] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Revised: 04/07/2017] [Accepted: 05/12/2017] [Indexed: 12/15/2022]
Abstract
Hpn is a small histidine-rich cytoplasmic protein from Helicobacter pylori and has been recognized as a high-risk factor for several cancers including gastric cancer, colorectal cancer, and MALT lymphoma. However, the relationship between Hpn and cancers remains elusive. In this study, we discovered that Hpn protein effectively suppressed cell growth and induced apoptosis in hepatocellular carcinoma (HCC). A two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomics was performed to find the molecular targets of Hpn in HCC cells. It was identified that twelve proteins were differentially expressed, with USP5 being one of the most significantly downregulated protein. The P14ARF -P53 signaling was activated by USP5 knockdown in HCC cells. Furthermore, USP5 overexpression significantly rescued the suppressive effect of Hpn on the viability of HCC cells. In conclusion, our study suggests that Hpn plays apoptosis-inducing roles through suppressing USP5 expression and activating the P14ARF -P53 signaling. Therefore, Hpn may be a potential candidate for developing novel anti-HCC drugs.
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Affiliation(s)
- Yi Liu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong, P. R. China
| | - Wei-Mao Wang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, P. R. China
| | - Li-Yi Zou
- Department of Pharmacology, Guangdong Medical University, Dongguan, Guangdong
| | - Li Li
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong, P. R. China
| | - Lu Feng
- Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, P. R. China
| | - Ming-Zhu Pan
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong, P. R. China
| | - Min-Yi Lv
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Ying Cao
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Hua Wang
- Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, P. R. China
| | - Hsiang-Fu Kung
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, P. R. China.,Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, P. R. China
| | - Jian-Xin Pang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Wei-Ming Fu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Jin-Fang Zhang
- Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, P. R. China.,School of medicine, South China Unversity of Technlogy, Guangzhou, P. R. China
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26
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Cairns MT, Gupta A, Naughton JA, Kane M, Clyne M, Joshi L. Glycosylation-related gene expression in HT29-MTX-E12 cells upon infection by Helicobacter pylori. World J Gastroenterol 2017; 23:6817-6832. [PMID: 29085225 PMCID: PMC5645615 DOI: 10.3748/wjg.v23.i37.6817] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Revised: 06/09/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To identify glycosylation-related genes in the HT29 derivative cell line, HT29-MTX-E12, showing differential expression on infection with Helicobacter pylori (H. pylori). METHODS Polarised HT29-MTX-E12 cells were infected for 24 h with H. pylori strain 26695. After infection RNA was isolated from both infected and non-infected host cells. Sufficient infections were carried out to provide triplicate samples for microarray analysis and for qRT-PCR analysis. RNA was isolated and hybridised to Affymetrix arrays. Analysis of microarray data identified genes significantly differentially expressed upon infection. Genes were grouped into gene ontology functional categories. Selected genes associated with host glycan structure (glycosyltransferases, hydrolases, lectins, mucins) were validated by real-time qRT-PCR analysis. RESULTS Infection of host cells was confirmed by the isolation of live bacteria after 24 h incubation and by PCR amplification of bacteria-specific genes from the host cell RNA. H. pylori do not survive incubation under the adopted culture conditions unless they associate with the adherent mucus layer of the host cell. Microarray analysis identified a total of 276 genes that were significantly differentially expressed (P < 0.05) upon H. pylori infection and where the fold change in expression was greater than 2. Six of these genes are involved in glycosylation-related processes. Real-time qRT-PCR demonstrated significant downregulation (1.8-fold, P < 0.05) of the mucin MUC20. REG4 was heavily expressed and significantly downregulated (3.1-fold, P < 0.05) upon infection. Gene ontology analysis was consistent with previous studies on H. pylori infection. CONCLUSION Gene expression data suggest that infection with H. pylori causes a decrease in glycan synthesis, resulting in shorter and simpler glycan structures.
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Affiliation(s)
- Michael T Cairns
- Glycoscience Group, National Centre for Biomedical Engineering Science, National University of Ireland Galway, H91 CF50 Galway, Ireland
| | - Ananya Gupta
- School of Natural Sciences, National University of Ireland Galway, H91 CF50 Galway, Ireland
| | - Julie A Naughton
- Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland
| | - Marian Kane
- Glycoscience Group, National Centre for Biomedical Engineering Science, National University of Ireland Galway, H91 CF50 Galway, Ireland
| | - Marguerite Clyne
- Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland
| | - Lokesh Joshi
- Glycoscience Group, National Centre for Biomedical Engineering Science, National University of Ireland Galway, H91 CF50 Galway, Ireland
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27
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Mejías-Luque R, Gerhard M. Immune Evasion Strategies and Persistence of Helicobacter pylori. Curr Top Microbiol Immunol 2017; 400:53-71. [PMID: 28124149 DOI: 10.1007/978-3-319-50520-6_3] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori infection is commonly acquired during childhood, can persist lifelong if not treated, and can cause different gastric pathologies, including chronic gastritis, peptic ulcer disease, and eventually gastric cancer. H. pylori has developed a number of strategies in order to cope with the hostile conditions found in the human stomach as well as successful mechanisms to evade the strong innate and adaptive immune responses elicited upon infection. Thus, by manipulating innate immune receptors and related signaling pathways, inducing tolerogenic dendritic cells and inhibiting effector T cell responses, H. pylori ensures low recognition by the host immune system as well as its persistence in the gastric epithelium. Bacterial virulence factors such as cytotoxin-associated gene A, vacuolating cytotoxin A, or gamma-glutamyltranspeptidase have been extensively studied in the context of bacterial immune escape and persistence. Further, the bacterium possesses other factors that contribute to immune evasion. In this chapter, we discuss in detail the main evasion and persistence strategies evolved by the bacterium as well as the specific bacterial virulence factors involved.
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Affiliation(s)
- Raquel Mejías-Luque
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany. .,German Centre for Infection Research (DZIF), Partner Site Munich, Munich, Germany.
| | - Markus Gerhard
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany.,German Centre for Infection Research (DZIF), Partner Site Munich, Munich, Germany
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28
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Nemati M, Larussa T, Khorramdelazad H, Mahmoodi M, Jafarzadeh A. Toll-like receptor 2: An important immunomodulatory molecule during Helicobacter pylori infection. Life Sci 2017; 178:17-29. [PMID: 28427896 DOI: 10.1016/j.lfs.2017.04.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Revised: 04/06/2017] [Accepted: 04/11/2017] [Indexed: 12/11/2022]
Abstract
Toll like receptors (TLRs) are an essential subset of pathogen recognition receptors (PRRs) which identify the microbial components and contribute in the regulation of innate and adaptive immune responses against the infectious agents. The TLRs, especially TLR2, TLR4, TLR5 and TLR9, participate in the induction of immune response against H. pylori. TLR2 is expressed on a number of immune and non-immune cells and recognizes a vast broad of microbial components due to its potential to form heterodimers with other TLRs, including TLR1, TLR6 and TLR10. A number of H. pylori-related molecules may contribute to TLR2-dependent responses, including HP-LPS, HP-HSP60 and HP-NAP. TLR2 plays a pivotal role in regulation of immune response to H. pylori through activation of NF-κB and induction of cytokine expression in epithelial cells, monocytes/macrophages, dendritic cells, neutrophils and B cells. The TLR2-related immune response that is induced by H. pylori-derived components may play an important role regarding the outcome of the infection toward bacterial elimination, persistence or pathological reactions. The immunomodulatory and immunoregulatory roles of TLR2 during H. pylori infection were considered in this review. TLR2 could be considered as an interesting therapeutic target for treatment of H. pylori-related diseases.
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Affiliation(s)
- Maryam Nemati
- Department of Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran; Department of Microbiology, School of Medicine, Islamic Azad University Branch of Kerman, Kerman, Iran
| | - Tiziana Larussa
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy
| | - Hossein Khorramdelazad
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Merat Mahmoodi
- Department of Immunology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abdollah Jafarzadeh
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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29
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Chmiela M, Karwowska Z, Gonciarz W, Allushi B, Stączek P. Host pathogen interactions in Helicobacter pylori related gastric cancer. World J Gastroenterol 2017; 23:1521-1540. [PMID: 28321154 PMCID: PMC5340805 DOI: 10.3748/wjg.v23.i9.1521] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 10/26/2016] [Accepted: 02/16/2017] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori), discovered in 1982, is a microaerophilic, spiral-shaped gram-negative bacterium that is able to colonize the human stomach. Nearly half of the world's population is infected by this pathogen. Its ability to induce gastritis, peptic ulcers, gastric cancer and mucosa-associated lymphoid tissue lymphoma has been confirmed. The susceptibility of an individual to these clinical outcomes is multifactorial and depends on H. pylori virulence, environmental factors, the genetic susceptibility of the host and the reactivity of the host immune system. Despite the host immune response, H. pylori infection can be difficult to eradicate. H. pylori is categorized as a group I carcinogen since this bacterium is responsible for the highest rate of cancer-related deaths worldwide. Early detection of cancer can be lifesaving. The 5-year survival rate for gastric cancer patients diagnosed in the early stages is nearly 90%. Gastric cancer is asymptomatic in the early stages but always progresses over time and begins to cause symptoms when untreated. In 97% of stomach cancer cases, cancer cells metastasize to other organs. H. pylori infection is responsible for nearly 60% of the intestinal-type gastric cancer cases but also influences the development of diffuse gastric cancer. The host genetic susceptibility depends on polymorphisms of genes involved in H. pylori-related inflammation and the cytokine response of gastric epithelial and immune cells. H. pylori strains differ in their ability to induce a deleterious inflammatory response. H. pylori-driven cytokines accelerate the inflammatory response and promote malignancy. Chronic H. pylori infection induces genetic instability in gastric epithelial cells and affects the DNA damage repair systems. Therefore, H. pylori infection should always be considered a pro-cancerous factor.
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30
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Smith SM, Freeley M, Moynagh PN, Kelleher DP. Differential modulation of Helicobacter pylori lipopolysaccharide-mediated TLR2 signaling by individual Pellino proteins. Helicobacter 2017; 22. [PMID: 27302665 DOI: 10.1111/hel.12325] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Eradication rates for current H. pylori therapies have fallen in recent years, in line with the emergence of antibiotic resistant infections. The development of therapeutic alternatives to antibiotics, such as immunomodulatory therapy and vaccines, requires a more lucid understanding of host-pathogen interactions, including the relationships between the organism and the innate immune response. Pellino proteins are emerging as key regulators of immune signaling, including the Toll-like receptor pathways known to be regulated by H. pylori. The aim of this study was to characterize the role of Pellino proteins in the innate immune response to H. pylori lipopolysaccharide. MATERIALS AND METHODS Gain-of-function and loss-of-function approaches were utilized to elucidate the role of individual Pellino proteins in the Toll-like receptor 2-mediated response to H. pylori LPS by monitoring NF-ĸB activation and the induction of proinflammatory chemokines. Expression of Pellino family members was investigated in gastric epithelial cells and gastric tissue biopsy material. RESULTS Pellino1 and Pellino2 positively regulated Toll-like receptor 2-driven responses to H. pylori LPS, whereas Pellino3 exerted a negative modulatory role. Expression of Pellino1 was significantly higher than Pellino3 in gastric epithelial cells and gastric tissue. Furthermore, Pellino1 expression was further augmented in gastric epithelial cells in response to infection with H. pylori or stimulation with H. pylori LPS. CONCLUSIONS The combination of low Pellino3 levels together with high and inducible Pellino1 expression may be an important determinant of the degree of inflammation triggered upon Toll-like receptor 2 engagement by H. pylori and/or its components, contributing to H. pylori-associated pathogenesis by directing the incoming signal toward an NF-kB-mediated proinflammatory response.
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Affiliation(s)
- Sinéad M Smith
- Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland.,School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland
| | - Michael Freeley
- Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Paul N Moynagh
- Institute of Immunology, National University of Ireland, Maynooth, Co. Kildare, Ireland
| | - Dermot P Kelleher
- Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland
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31
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Tran CT, Garcia M, Garnier M, Burucoa C, Bodet C. Inflammatory signaling pathways induced by Helicobacter pylori in primary human gastric epithelial cells. Innate Immun 2016; 23:165-174. [DOI: 10.1177/1753425916681077] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Inflammatory signaling pathways induced by Helicobacter pylori remain unclear, having been studied mostly on cell-line models derived from gastric adenocarcinoma with potentially altered signaling pathways and nonfunctional receptors. Here, H. pylori-induced signaling pathways were investigated in primary human gastric epithelial cells. Inflammatory response was analyzed on chemokine mRNA expression and production after infection of gastric epithelial cells by H. pylori strains, B128 and B128Δ cagM, a cag type IV secretion system defective strain. Signaling pathway involvement was investigated using inhibitors of epidermal growth factor receptor (EGFR), MAPK, JAK and blocking Abs against TLR2 and TLR4. Inhibitors of EGFR, MAPK and JAK significantly reduced the chemokine mRNA expression and production induced by both H. pylori strains at 3 h and 24 h post-infection. JNK inhibitor reduced chemokine production at 24 h post-infection. Blocking Abs against TLR2 but not TLR4 showed significant reduction of chemokine secretion. Using primary culture of human gastric epithelial cells, our data suggest that H. pylori can be recognized by TLR2, leading to chemokine induction, and that EGFR, MAPK and the JAK/STAT signaling pathways play a key role in the H. pylori-induced CXCL1, CXCL5 and CXCL8 response in a cag pathogenicity island-independent manner.
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Affiliation(s)
- Cong Tri Tran
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines (LITEC - EA 4331), Université de Poitiers, Poitiers, France
- Laboratoire de Bactériologie Hygiène, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Magali Garcia
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines (LITEC - EA 4331), Université de Poitiers, Poitiers, France
- Laboratoire de Bactériologie Hygiène, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Martine Garnier
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines (LITEC - EA 4331), Université de Poitiers, Poitiers, France
- Laboratoire de Bactériologie Hygiène, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Christophe Burucoa
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines (LITEC - EA 4331), Université de Poitiers, Poitiers, France
- Laboratoire de Bactériologie Hygiène, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Charles Bodet
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines (LITEC - EA 4331), Université de Poitiers, Poitiers, France
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32
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Li H, Liao T, Debowski AW, Tang H, Nilsson HO, Stubbs KA, Marshall BJ, Benghezal M. Lipopolysaccharide Structure and Biosynthesis in Helicobacter pylori. Helicobacter 2016; 21:445-461. [PMID: 26934862 DOI: 10.1111/hel.12301] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
This review covers the current knowledge and gaps in Helicobacter pylori lipopolysaccharide (LPS) structure and biosynthesis. H. pylori is a Gram-negative bacterium which colonizes the luminal surface of the human gastric epithelium. Both a constitutive alteration of the lipid A preventing TLR4 elicitation and host mimicry of the Lewis antigen decorated O-antigen of H. pylori LPS promote immune escape and chronic infection. To date, the complete structure of H. pylori LPS is not available, and the proposed model is a linear arrangement composed of the inner core defined as the hexa-saccharide (Kdo-LD-Hep-LD-Hep-DD-Hep-Gal-Glc), the outer core composed of a conserved trisaccharide (-GlcNAc-Fuc-DD-Hep-) linked to the third heptose of the inner core, the glucan, the heptan and a variable O-antigen, generally consisting of a poly-LacNAc decorated with Lewis antigens. Although the glycosyltransferases (GTs) responsible for the biosynthesis of the H. pylori O-antigen chains have been identified and characterized, there are many gaps in regard to the biosynthesis of the core LPS. These limitations warrant additional mutagenesis and structural studies to obtain the complete LPS structure and corresponding biosynthetic pathway of this important gastric bacterium.
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Affiliation(s)
- Hong Li
- West China Marshall Research Centre for Infectious Diseases, Centre of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China.,Helicobacter pylori Research Laboratory, School of Pathology & Laboratory Medicine, Marshall Centre for Infectious Disease Research and Training, The University of Western Australia, M504, L Block, QEII Medical Centre, Nedlands, WA 6009, Australia
| | - Tingting Liao
- Helicobacter pylori Research Laboratory, School of Pathology & Laboratory Medicine, Marshall Centre for Infectious Disease Research and Training, The University of Western Australia, M504, L Block, QEII Medical Centre, Nedlands, WA 6009, Australia
| | - Aleksandra W Debowski
- Helicobacter pylori Research Laboratory, School of Pathology & Laboratory Medicine, Marshall Centre for Infectious Disease Research and Training, The University of Western Australia, M504, L Block, QEII Medical Centre, Nedlands, WA 6009, Australia.,School of Chemistry and Biochemistry, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia
| | - Hong Tang
- West China Marshall Research Centre for Infectious Diseases, Centre of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Hans-Olof Nilsson
- Ondek Pty Ltd., School of Pathology & Laboratory Medicine, Marshall Centre for Infectious Disease Research and Training, The University of Western Australia, M504, L Block, QEII Medical Centre, Nedlands, WA 6009, Australia
| | - Keith A Stubbs
- School of Chemistry and Biochemistry, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia
| | - Barry J Marshall
- Helicobacter pylori Research Laboratory, School of Pathology & Laboratory Medicine, Marshall Centre for Infectious Disease Research and Training, The University of Western Australia, M504, L Block, QEII Medical Centre, Nedlands, WA 6009, Australia
| | - Mohammed Benghezal
- Helicobacter pylori Research Laboratory, School of Pathology & Laboratory Medicine, Marshall Centre for Infectious Disease Research and Training, The University of Western Australia, M504, L Block, QEII Medical Centre, Nedlands, WA 6009, Australia.,Swiss Vitamin Institute, Route de la Corniche 1, CH-1066, Epalinges, Switzerland
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Hu Y, Liu JP, Zhu Y, Lu NH. The Importance of Toll-like Receptors in NF-κB Signaling Pathway Activation by Helicobacter pylori Infection and the Regulators of this Response. Helicobacter 2016; 21:428-40. [PMID: 26763943 DOI: 10.1111/hel.12292] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Helicobacter pylori (H. pylori) is a common pathogenic bacterium in the stomach that infects almost half of the population worldwide and is closely related to gastric diseases and some extragastric diseases, including iron-deficiency anemia and idiopathic thrombocytopenic purpura. Both the Maastricht IV/Florence consensus report and the Kyoto global consensus report have proposed the eradication of H. pylori to prevent gastric cancer as H.pylori has been shown to be a major cause of gastric carcinogenesis. The interactions between H. pylori and host receptors induce the release of the proinflammatory cytokines by activating proinflammatory signaling pathways such as nuclear factor kappa B (NF-κB), which plays a central role in inflammation, immune response, and carcinogenesis. Among these receptors, Toll-like receptors (TLRs) are classical pattern recognition receptors in the recognition of H. pylori and the mediation of the host inflammatory and immune responses to H. pylori. TLR polymorphisms also contribute to the clinical consequences of H. pylori infection. In this review, we focus on the functions of TLRs in the NF-κB signaling pathway activated by H. pylori, the regulators modulating this response, and the functions of TLR polymorphisms in H.pylori-related diseases.
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Affiliation(s)
- Yi Hu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jian-Ping Liu
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
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Abstract
Tribbles (TRIB) proteins, a family of evolutionary conserved psuedokinase proteins, modulate various signalling pathways within the cell. The regulatory roles of TRIB make them an important part of a number of biological processes ranging from cell proliferation to metabolism, immunity, inflammation and carcinogenesis. Innate immune system plays a pivotal role during the regulation of reproductive processes that allows successful creation of an offspring. Its involvement initiates from fertilization of the oocyte by spermatozoon and lasts throughout early embryonic development, pregnancy and labour. Therefore, there is a close cooperation between the reproductive system and the innate immune system. Evidence from our lab has demonstrated that improper activation of the innate immune system can reduce embryo implantation, thus leading to infertility. Therefore, control mechanisms regulating the innate immune system function can be critical for successful reproductive events.
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35
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Mondal D, Mathur A, Chandra PK. Tripping on TRIB3 at the junction of health, metabolic dysfunction and cancer. Biochimie 2016; 124:34-52. [DOI: 10.1016/j.biochi.2016.02.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 02/04/2016] [Indexed: 12/16/2022]
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36
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Kronsteiner B, Bassaganya-Riera J, Philipson C, Viladomiu M, Carbo A, Abedi V, Hontecillas R. Systems-wide analyses of mucosal immune responses to Helicobacter pylori at the interface between pathogenicity and symbiosis. Gut Microbes 2016; 7:3-21. [PMID: 26939848 PMCID: PMC4856448 DOI: 10.1080/19490976.2015.1116673] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 10/29/2015] [Accepted: 10/31/2015] [Indexed: 02/08/2023] Open
Abstract
Helicobacter pylori is the dominant member of the gastric microbiota in over half of the human population of which 5-15% develop gastritis or gastric malignancies. Immune responses to H. pylori are characterized by mixed T helper cell, cytotoxic T cell and NK cell responses. The presence of Tregs is essential for the control of gastritis and together with regulatory CX3CR1+ mononuclear phagocytes and immune-evasion strategies they enable life-long persistence of H. pylori. This H. pylori-induced regulatory environment might contribute to its cross-protective effect in inflammatory bowel disease and obesity. Here we review host-microbe interactions, the development of pro- and anti-inflammatory immune responses and how the latter contribute to H. pylori's role as beneficial member of the gut microbiota. Furthermore, we present the integration of existing and new data into a computational/mathematical model and its use for the investigation of immunological mechanisms underlying initiation, progression and outcomes of H. pylori infection.
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Affiliation(s)
- Barbara Kronsteiner
- Nutritional Immunology and Molecular Medicine Laboratory and Center for Modeling Immunity to Enteric Pathogens; Virginia Bioinformatics Institute; Virginia Tech; Blacksburg, VA, USA
| | - Josep Bassaganya-Riera
- Nutritional Immunology and Molecular Medicine Laboratory and Center for Modeling Immunity to Enteric Pathogens; Virginia Bioinformatics Institute; Virginia Tech; Blacksburg, VA, USA
| | | | - Monica Viladomiu
- Nutritional Immunology and Molecular Medicine Laboratory and Center for Modeling Immunity to Enteric Pathogens; Virginia Bioinformatics Institute; Virginia Tech; Blacksburg, VA, USA
| | | | - Vida Abedi
- Nutritional Immunology and Molecular Medicine Laboratory and Center for Modeling Immunity to Enteric Pathogens; Virginia Bioinformatics Institute; Virginia Tech; Blacksburg, VA, USA
| | - Raquel Hontecillas
- Nutritional Immunology and Molecular Medicine Laboratory and Center for Modeling Immunity to Enteric Pathogens; Virginia Bioinformatics Institute; Virginia Tech; Blacksburg, VA, USA
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Association between the TLR2 Arg753Gln polymorphism and the risk of sepsis: a meta-analysis. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2015; 19:416. [PMID: 26616674 PMCID: PMC4663740 DOI: 10.1186/s13054-015-1130-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 11/04/2015] [Indexed: 01/07/2023]
Abstract
Introduction Recently, researchers in a number of studies have explored the association between the Toll-like receptor 2 (TLR2) Arg753Gln polymorphism and sepsis risk. However, the results were conflicting. In this meta-analysis, we aimed to confirm the effect of the TLR2 Arg753Gln polymorphism on sepsis risk. Methods Relevant records up to 1 June 2015 were retrieved from the PubMed, Embase, and Web of Knowledge databases. The odds ratios with their corresponding 95 % confidence intervals were used to assess the association between the TLR2 Arg753Gln polymorphism and sepsis risk. The selection of a fixed or random effects model was made according to a heterogeneity test in total and subgroup analyses. Sensitivity analysis and publication bias test were performed to ensure the reliability of our results. Results A total of 12 studies with aggregate totals of 898 cases and 1517 controls met our inclusion criteria for meta-analysis. There were significant associations between the TLR2 Arg753Gln polymorphism and sepsis risk in overall analyses under two genetic models (the allele comparison and the dominant model). In addition, subgroup analyses based on age group, ethnicity, sepsis type, and source of control also showed a significant effect of the TLR2 Arg753Gln polymorphism on sepsis risk. Conclusions Our present meta-analysis supports a direct effect of the TLR2 Arg753Gln polymorphism on sepsis risk, especially in Europeans. The TLR2 Arg753Gln polymorphism might be used as a relevant risk estimate for the development of sepsis. Studies with larger sample sizes and homogeneous groups of patients with sepsis are required for further analysis. Electronic supplementary material The online version of this article (doi:10.1186/s13054-015-1130-3) contains supplementary material, which is available to authorized users.
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White JR, Winter JA, Robinson K. Differential inflammatory response to Helicobacter pylori infection: etiology and clinical outcomes. J Inflamm Res 2015; 8:137-47. [PMID: 26316793 PMCID: PMC4540215 DOI: 10.2147/jir.s64888] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The bacterial pathogen Helicobacter pylori commonly colonizes the human gastric mucosa during early childhood and persists throughout life. The organism has evolved multiple mechanisms for evading clearance by the immune system and, despite inducing inflammation in the stomach, the majority of infections are asymptomatic. H. pylori is the leading cause of peptic ulcer disease and gastric cancer. However, disease outcomes are related to the pattern and severity of chronic inflammation in the gastric mucosa, which in turn is influenced by both bacterial and host factors. Despite over 2 decades of intensive research, there remains an incomplete understanding of the circumstances leading to disease development, due to the fascinating complexity of the host-pathogen interactions. There is accumulating data concerning the virulence factors associated with increased risk of disease, and the majority of these have pro-inflammatory activities. Despite this, only a small proportion of those infected with virulent strains develop disease. Several H. pylori virulence factors have multiple effects on different cell types, including the induction of pro- and anti-inflammatory, immune stimulatory, and immune modulatory responses. The expression of multiple virulence factors is also often linked, making it difficult to assess the meaning of their effects in isolation. Overall, H. pylori is thought to usually modulate inflammation and limit acute damage to the mucosa, enabling the bacteria to persist. If this delicate balance is disturbed, disease may then develop.
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Affiliation(s)
- Jonathan Richard White
- NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals NHS Trust and The University of Nottingham, Nottingham, UK
| | - Jody Anne Winter
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Karen Robinson
- NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals NHS Trust and The University of Nottingham, Nottingham, UK
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Yu HJ, Liu W, Chang Z, Shen H, He LJ, Wang SS, Liu L, Jiang YY, Xu GT, An MM, Zhang JD. Probiotic BIFICO cocktail ameliorates Hel icobacter pylori induced gastritis. World J Gastroenterol 2015; 21:6561-6571. [PMID: 26074694 PMCID: PMC4458766 DOI: 10.3748/wjg.v21.i21.6561] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Revised: 02/05/2015] [Accepted: 03/12/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the protective effect of triple viable probiotics on gastritis induced by Helicobacter pylori (H. pylori) and elucidate the possible mechanisms of protection.
METHODS: Colonization of BIFICO strains in the mouse stomach was determined by counting colony-forming units per gram of stomach tissue. After treatment with or without BIFICO, inflammation and H. pylori colonization in the mouse stomach were analyzed by hematoxylin and eosin and Giemsa staining, respectively. Cytokine levels were determined by enzyme-linked immunosorbent assay and Milliplex. The activation of nuclear factor (NF)-κB and MAPK signaling in human gastric epithelial cells was evaluated by Western blot analysis. Quantitative reverse transcription-polymerase chain reaction was used to quantify TLR2, TLR4 and MyD88 mRNA expression in the mouse stomach.
RESULTS: We demonstrated that BIFICO, which contains a mixture of Enterococcus faecalis, Bifidobacterium longum and Lactobacillus acidophilus, was tolerant to the mouse stomach environment and was able to survive both the 8-h and 3-d courses of administration. Although BIFICO treatment had no effect on the colonization of H. pylori in the mouse stomach, it ameliorated H. pylori-induced gastritis by significantly inhibiting the expression of cytokines and chemokines such as TNF-α, IL-1β, IL-10, IL-6, G-CSF and MIP-2 (P < 0.05). These results led us to hypothesize that BIFICO treatment would diminish the H. pylori-induced inflammatory response in gastric mucosal epithelial cells in vitro via the NF-κB and MAPK signaling pathways. Indeed, we observed a decrease in the expression of the NF-κB subunit p65 and in the phosphorylation of IκB-α, ERK and p38. Moreover, there was a significant decrease in the production of IL-8, TNF-α, G-CSF and GM-CSF (P < 0.05), and the increased expression of TLR2, TLR4 and MyD88 induced by H. pylori in the stomach was also significantly reduced following BIFICO treatment (P < 0.05).
CONCLUSION: Our results suggest that the probiotic cocktail BIFICO can ameliorate H. pylori-induced gastritis by inhibiting the inflammatory response in gastric epithelial cells.
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Nagashima H, Iwatani S, Cruz M, Jiménez Abreu JA, Uchida T, Mahachai V, Vilaichone RK, Graham DY, Yamaoka Y. Toll-like Receptor 10 in Helicobacter pylori Infection. J Infect Dis 2015; 212:1666-76. [PMID: 25977263 DOI: 10.1093/infdis/jiv270] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 04/10/2015] [Indexed: 12/20/2022] Open
Abstract
Innate immunity plays important roles in the primary defense against pathogens, and epidemiological studies have suggested a role for Toll-like receptor 1 (TLR1) in Helicobacter pylori susceptibility. Microarray analysis of gastric biopsy specimens from H. pylori-positive and uninfected subjects showed that TLR10 messenger RNA (mRNA) levels were upregulated approximately 15-fold in infected subjects; these findings were confirmed by real-time quantitative polymerase chain reaction analysis. Immunohistochemical investigation showed increased TLR10 expression in the gastric epithelial cells of infected individuals. When H. pylori was cocultured with NCI-N87 gastric cells, both TLR10 and TLR2 mRNA levels were upregulated. We compared the ability of TLR combinations to mediate nuclear factor-κB (NF-κB) activation. Compared with other TLR2 subfamily heterodimers, the TLR2/TLR10 heterodimer mediated the greatest NF-κB activation following exposure to heat-killed H. pylori or H. pylori lipopolysaccharide. We conclude that TLR10 is a functional receptor involved in the innate immune response to H. pylori infection and that the TLR2/TLR10 heterodimer functions in H. pylori lipopolysaccharide recognition.
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Affiliation(s)
- Hiroyuki Nagashima
- Department of Environmental and Preventive Medicine Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas
| | - Shun Iwatani
- Department of Environmental and Preventive Medicine Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas
| | - Modesto Cruz
- Institute of Microbiology and Parasitology, Department of Science, Autonomous University of Santo Domingo Department of Biomedical Research, School of Medicine, Santiago Technological University
| | - José A Jiménez Abreu
- Dominican-Japanese Digestive Disease Center, Dr Luis E. Aybar Health and Hygiene City, Santo Domingo, Dominican Republic
| | - Tomohisa Uchida
- Department of Molecular Pathology, Oita University Faculty of Medicine, Yufu, Japan
| | - Varocha Mahachai
- Gastroenterology Unit, Department of Medicine, Thammasat University Hospital, Pathumthani
| | | | - David Y Graham
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas
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Yu Y, Qiu L, Guo J, Yang D, Qu L, Yu J, Zhan F, Xue M, Zhong M. TRIB3 mediates the expression of Wnt5a and activation of nuclear factor-κB in Porphyromonas endodontalis lipopolysaccharide-treated osteoblasts. Mol Oral Microbiol 2015; 30:295-306. [PMID: 25601649 DOI: 10.1111/omi.12094] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2015] [Indexed: 12/25/2022]
Abstract
Porphyromonas endodontalis lipopolysaccharide (LPS) is considered to be correlated with the progression of bone resorption in periodontal and periapical diseases. Wnt5a has recently been implicated in inflammatory processes, but its role is unclear as a P. endodontalis LPS-induced mediator in osteoblasts. Tribbles homolog 3 (TRIB3) encodes a pseudokinase and has been linked to inflammation in certain situations. Here, we found that P. endodontalis LPS induced Wnt5a expression in a dose- and time-dependent manner and it also upregulated translocation, phosphorylation and transcriptional activity of nuclear factor-κB (NF-κB) in MC3T3-E1 cells. Bay 11-7082 blocked the translocation of NF-κB and Wnt5a expression induced by P. endodontalis LPS. Chromatin immunoprecipitation assay further established that induction of Wnt5a by P. endodontalis LPS was mediated through the NF-κB p65 subunit. Additionally, P. endodontalis LPS increased expression of TRIB3 in osteoblasts after 10 h simulated time. Overexpression of TRIB3 enhanced NF-κB phosphorylation and Wnt5a induction, whereas knockdown of TRIB3 inhibited NF-κB phosphorylation and Wnt5a expression in P. endodontalis LPS-stimulated osteoblasts. These results suggest that P. endodontalis LPS has the ability to promote the expression of Wnt5a in mouse osteoblasts, and this induction is mainly mediated by NF-κB pathway. TRIB3 seems to modulate the sustained expression of Wnt5a in osteoblasts stimulated by P. endodontalis LPS, as well as regulating NF-κB phosphorylation.
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Affiliation(s)
- Y Yu
- Department of Endodontics, School of Stomatology, China Medical University, Shenyang, China
| | - L Qiu
- Department of Endodontics, School of Stomatology, China Medical University, Shenyang, China
| | - J Guo
- Department of Endodontics, School of Stomatology, China Medical University, Shenyang, China
| | - D Yang
- Department of Endodontics, School of Stomatology, China Medical University, Shenyang, China
| | - L Qu
- Department of Endodontics, School of Stomatology, China Medical University, Shenyang, China
| | - J Yu
- Department of Endodontics, School of Stomatology, China Medical University, Shenyang, China
| | - F Zhan
- Department of Endodontics, School of Stomatology, China Medical University, Shenyang, China
| | - M Xue
- Department of Endodontics, School of Stomatology, China Medical University, Shenyang, China
| | - M Zhong
- Department of Oral Pathology, Central Laboratory, School of Stomatology, China Medical University, Shenyang, China
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Kondadi PK, Revez J, Hänninen ML, Rossi M. Sialylation of Helicobacter bizzozeronii lipopolysaccharides modulates Toll-like receptor (TLR) 2 mediated response. Vet Res 2015; 46:4. [PMID: 25603825 PMCID: PMC4299687 DOI: 10.1186/s13567-014-0133-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 12/10/2014] [Indexed: 12/20/2022] Open
Abstract
Sialic acid in lipopolysaccharides (LPS) of mucosal pathogens is known to be an important virulence factor. Few strains of Helicobacter pylori express sialyl-Lewis-X and we have reported that human and canine Helicobacter bizzozeronii strains express sialyl-lactoseamine in their LPS. However, the role of sialyation of Helicobacter LPS in the interaction with the host cells is still unknown. In this study H. bizzozeronii LPS is shown to activate the TLR2 in a dose and strain dependent manner in the in vitro HEK-293 cells model expressing TLR2, but not the cells expressing TLR4. These results indicate that TLR2 is the specific receptor for H. bizzozzeronii LPS, as previously described for H. pylori. To further explore the role of sialylation of H. bizzozeronii LPS on TLR2 response, H. bizzozeronii Δhbs2 mutant strains deficient in sialyltransferase activity were constructed by homologous recombination. LPS from H. bizzozeronii Δhbs2 strains enhanced the NF-ĸB induction via TLR2 compared to the respective wild types, leading to the conclusion that the sialylation of H. bizzozeronii LPS in wild-type strains may modulate host immune response.
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Affiliation(s)
| | | | | | - Mirko Rossi
- Department of Food Hygiene and Environmental Health, Faculty of Veterinary Medicine, University of Helsinki, Agnes Sjöbergin katu 2, Helsinki, FI-00014, Finland.
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Wang XJ, Luo Y, Yu B, Hu SJ, Du ZH, Yin J, Xia R. Effect of Mieyou decoction on TLRs/NF-κB65 signal pathway in mice with Helicobacter pylori associated gastritis with splenogastric hygropyrexia syndrome. Shijie Huaren Xiaohua Zazhi 2014; 22:3371-3379. [DOI: 10.11569/wcjd.v22.i23.3371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the gastric expression of Toll-like receptor 2 (TLR2), TLR4, nuclear factor-kappa B 65 (NF-κB65), and serum levels of interleukin-6 (IL-6) and IL-8 in mice with Helicobacter pylori (H. pylori) associated gastritis with splenogastric hygropyrexia syndrome (SGHS), and to investigate the mechanism underlying the therapeutic effect of Mieyou decoction in the treatment of chronic gastritis.
METHODS: BALB/c mouse were randomly divided into five groups: a control group, a model group, a high-concentration Mieyou decoction group, a low-concentrations Mieyou decoction group, and a triple therapy group (tinidazole, clarithromycin and bismuth potassium citrate granules), with 14 rats in each group. The BALB/c model of H. pylori-associated gastritis with SGHS using a composite method (fatness food + hygropyrexia environment + H. pylori). After the success of modeling, continuous administration 14 d. Immunohistochemistry was used to detect the expression TLR2, TLR4 and NF-κB65 proteins in gastric tissue; qPCR was used to detect the expression of TLR2, TLR4 and NF-κB65 mRNAs; ELISA was used to detect the levels of IL-6 and IL-8 in serum.
RESULTS: Compared with the control group, the expression of TLR2, TLR4, NF-κB65 proteins and mRNAs, and serum levels of IL-6 and IL-8 in the model group were significantly increased. After therapy, the expression of TLR2, TLR4, NF-κB65 proteins and mRNAs, and serum levels of IL-6 and IL-8 in the high-concentration Mieyou decoction group, low-concentration Mieyou decoction group, and triple therapy group were significantly decreased compared with the model group. The expression of TLR2, TLR4, NF-κB65 proteins and mRNAs, and serum levels of IL-6 and IL-8 in the high-concentration Mieyou decoction group were higher than those in the triple therapy group, but the differences were not statistically significant.
CONCLUSION: Mieyou decoction has a role in the treatment of H. pylori-associated gastritis with SGHS possibly by intervening the TLRs/NF-κB65 signal pathway.
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Smith SM. Role of Toll-like receptors in Helicobacter pylori infection and immunity. World J Gastrointest Pathophysiol 2014; 5:133-146. [PMID: 25133016 PMCID: PMC4133513 DOI: 10.4291/wjgp.v5.i3.133] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 02/25/2014] [Accepted: 05/19/2014] [Indexed: 02/07/2023] Open
Abstract
The gram-negative bacterium Helicobacter pylori (H. pylori) infects the stomachs of approximately half of the world’s population. Although infection induces an immune response that contributes to chronic gastric inflammation, the response is not sufficient to eliminate the bacterium. H. pylori infection causes peptic ulcers, gastric cancer and mucosa-associated lymphoid tissue lymphoma. Disease outcome is linked to the severity of the host inflammatory response. Gastric epithelial cells represent the first line of innate immune defence against H. pylori, and respond to infection by initiating numerous cell signalling cascades, resulting in cytokine induction and the subsequent recruitment of inflammatory cells to the gastric mucosa. Pathogen recognition receptors of the Toll-like receptor (TLR) family mediate many of these cell signalling events. This review discusses recent findings on the role of various TLRs in the recognition of H. pylori in distinct cell types, describes the TLRs responsible for the recognition of individual H. pylori components and outlines the influence of innate immune activation on the subsequent development of the adaptive immune response. The mechanistic identification of host mediators of H. pylori-induced pathogenesis has the potential to reveal drug targets and opportunities for therapeutic intervention or prevention of H. pylori-associated disease by means of vaccines or immunomodulatory therapy.
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Castaño-Rodríguez N, Kaakoush NO, Mitchell HM. Pattern-recognition receptors and gastric cancer. Front Immunol 2014; 5:336. [PMID: 25101079 PMCID: PMC4105827 DOI: 10.3389/fimmu.2014.00336] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 07/03/2014] [Indexed: 12/12/2022] Open
Abstract
Chronic inflammation has been associated with an increased risk of several human malignancies, a classic example being gastric adenocarcinoma (GC). Development of GC is known to result from infection of the gastric mucosa by Helicobacter pylori, which initially induces acute inflammation and, in a subset of patients, progresses over time to chronic inflammation, gastric atrophy, intestinal metaplasia, dysplasia, and finally intestinal-type GC. Germ-line encoded receptors known as pattern-recognition receptors (PRRs) are critical for generating mature pro-inflammatory cytokines that are crucial for both Th1 and Th2 responses. Given that H. pylori is initially targeted by PRRs, it is conceivable that dysfunction within genes of this arm of the immune system could modulate the host response against H. pylori infection, and subsequently influence the emergence of GC. Current evidence suggests that Toll-like receptors (TLRs) (TLR2, TLR3, TLR4, TLR5, and TLR9), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) (NOD1, NOD2, and NLRP3), a C-type lectin receptor (DC-SIGN), and retinoic acid-inducible gene (RIG)-I-like receptors (RIG-I and MDA-5), are involved in both the recognition of H. pylori and gastric carcinogenesis. In addition, polymorphisms in genes involved in the TLR (TLR1, TLR2, TLR4, TLR5, TLR9, and CD14) and NLR (NOD1, NOD2, NLRP3, NLRP12, NLRX1, CASP1, ASC, and CARD8) signaling pathways have been shown to modulate the risk of H. pylori infection, gastric precancerous lesions, and/or GC. Further, the modulation of PRRs has been suggested to suppress H. pylori-induced inflammation and enhance GC cell apoptosis, highlighting their potential relevance in GC therapeutics. In this review, we present current advances in our understanding of the role of the TLR and NLR signaling pathways in the pathogenesis of GC, address the involvement of other recently identified PRRs in GC, and discuss the potential implications of PRRs in GC immunotherapy.
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Affiliation(s)
- Natalia Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales , Sydney, NSW , Australia
| | - Nadeem O Kaakoush
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales , Sydney, NSW , Australia
| | - Hazel M Mitchell
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales , Sydney, NSW , Australia
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Uno K, Kato K, Shimosegawa T. Novel role of toll-like receptors in Helicobacter pylori - induced gastric malignancy. World J Gastroenterol 2014; 20:5244-51. [PMID: 24833854 PMCID: PMC4017039 DOI: 10.3748/wjg.v20.i18.5244] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 12/13/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infects the human stomach during infancy and develops into chronic active inflammation. The majority of H. pylori tend to colonize within the mucous gel layer of the stomach. The stomach lacks its own immune function, thus innate immunity as the first line of defense is vital for specific immunity against H. pylori. We review recent discoveries in the pathophysiologic roles of toll-like receptors (TLRs), mainly TLR2 and TLR4, in H. pylori-induced inflammation. In addition, the TLR pathways activated by H. pylori-induced inflammation have been shown to be closely associated not only with gastric carcinogenesis, but also with formation of the tumor microenvironment through the production of pro-inflammatory cytokines, chemokines, and reactive oxygen species. Although the correlation between single nucleotide polymorphisms of TLRs and gastric cancer risk remains unclear, a recent study demonstrated that STAT3-driven up-regulation of TLR2 might promote gastric tumorigenesis independent of inflammation. Further research on the regulation of TLRs in H. pylori-associated gastric carcinogenesis will uncover diagnostic/predictive biomarkers and therapeutic targets for gastric cancer.
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Chemokines and antimicrobial peptides have a cag-dependent early response to Helicobacter pylori infection in primary human gastric epithelial cells. Infect Immun 2014; 82:2881-9. [PMID: 24778119 DOI: 10.1128/iai.01517-13] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Helicobacter pylori infection systematically causes chronic gastric inflammation that can persist asymptomatically or evolve toward more severe gastroduodenal pathologies, such as ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. The cag pathogenicity island (cag PAI) of H. pylori allows translocation of the virulence protein CagA and fragments of peptidoglycan into host cells, thereby inducing production of chemokines, cytokines, and antimicrobial peptides. In order to characterize the inflammatory response to H. pylori, a new experimental protocol for isolating and culturing primary human gastric epithelial cells was established using pieces of stomach from patients who had undergone sleeve gastrectomy. Isolated cells expressed markers indicating that they were mucin-secreting epithelial cells. Challenge of primary epithelial cells with H. pylori B128 underscored early dose-dependent induction of expression of mRNAs of the inflammatory mediators CXCL1 to -3, CXCL5, CXCL8, CCL20, BD2, and tumor necrosis factor alpha (TNF-α). In AGS cells, significant expression of only CXCL5 and CXCL8 was observed following infection, suggesting that these cells were less reactive than primary epithelial cells. Infection of both cellular models with H. pylori B128ΔcagM, a cag PAI mutant, resulted in weak inflammatory-mediator mRNA induction. At 24 h after infection of primary epithelial cells with H. pylori, inflammatory-mediator production was largely due to cag PAI substrate-independent virulence factors. Thus, H. pylori cag PAI substrate appears to be involved in eliciting an epithelial response during the early phases of infection. Afterwards, other virulence factors of the bacterium take over in development of the inflammatory response. Using a relevant cellular model, this study provides new information on the modulation of inflammation during H. pylori infection.
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Kopitar AN, Skvarc M, Tepes B, Kos J, Ihan A. Helicobacter pylori susceptible/resistant to antibiotic eradication therapy differ in the maturation and activation of dendritic cells. Helicobacter 2013; 18:444-53. [PMID: 23859622 DOI: 10.1111/hel.12068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND The natural course of Helicobacter pylori infection, as well as the success of antibiotic eradication is determined by the immune response to bacteria. The aim of the study is to investigate how different Helicobacter pylori isolates influence the dendritic cells maturation and antigen-presenting function in order to elucidate the differences between Helicobacter pylori strains, isolated from the patients with successful antibiotic eradication therapy or repeated eradication failure. MATERIALS AND METHODS Dendritic cells maturation and antigen presentation were monitored by flow cytometry analysis of the major histocompatibility complex class II (MHC-II), Toll-like receptor (TLR) and costimulatory molecules expression, and by determining cytokine secretion. RESULTS Dendritic cells stimulated with Helicobacter pylori isolated from patients with repeated antibiotic eradication failure expressed less human leukocyte antigen (HLA-DR), CD86, TLR-2, and interleukin-8 (IL-8) compared to Helicobacter pylori strains susceptible to antibiotic therapy; the latter expressed lower production of IL-10. Polymyxin B inhibition of lipopolysaccharide reduces IL-8 secretion in the group of Helicobacter pylori strains susceptible to antibiotic therapy. The differences in IL-8 secretion between both groups are lipopolysaccharide dependent, while the differences in secretion of IL-10 remain unchanged after lipopolysaccharide inhibition. Inhibitor of cathepsin X Mab 2F12 reduced the secretion of IL-6, and the secretion was significantly lower in the group of Helicobacter pylori strains isolated from patients with repeated antibiotic eradication failure. CONCLUSION Helicobacter pylori strains, susceptible/resistant to antibiotic eradication therapy, differ in their capability to induce DCs maturation and antigen-presenting function.
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Affiliation(s)
- Andreja N Kopitar
- Medical Faculty Ljubljana, Institute of Microbiology and Immunology, University of Ljubljana, Ljubljana, Slovenia
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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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IRAK-M expression limits dendritic cell activation and proinflammatory cytokine production in response to Helicobacter pylori. PLoS One 2013; 8:e66914. [PMID: 23776703 PMCID: PMC3679069 DOI: 10.1371/journal.pone.0066914] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 05/10/2013] [Indexed: 12/12/2022] Open
Abstract
Helicobacter pylori (H. pylori) infects the gastric mucosa and persists for the life of the host. Bacterial persistence may be due to the induction of regulatory T cells (Tregs) whichmay have protective effects against other diseases such as asthma. It has been shown that H. pylori modulates the T cell response through dendritic cell reprogramming but the molecular pathways involved are relatively unknown. The goal of this study was to identify critical elements of dendritic cell (DC) activation and evaluate potential influence on immune activation. Microarray analysis was used to demonstrate limited gene expression changes in H. pylori stimulated bone marrow derived DCs (BMDCs) compared to the BMDCs stimulated with E. coli. IRAK-M, a negative regulator of TLR signaling, was upregulated and we selectedit for investigation of its role in modulating the DC and T cell responses. IRAK-M−/− and wild type BMDC were compared for their response to H. pylori. Cells lacking IRAK-M produced significantly greater amounts of proinflammatory MIP-2 and reduced amounts of immunomodulatory IL-10 than wild type BMDC. IRAK-M−/− cells also demonstrated increased MHC II expression upon activation. However, IRAK-M−/− BMDCs were comparable to wild type BMDCs in inducing T-helper 17 (TH17) and Treg responses as demonstrated in vitro using BMDC CD4+ T cells co-culture assays,and in vivo though the adoptive transfer of CD4+ FoxP3-GFP T cells into H. pylori infected IRAK-M−/− mice. These results suggest that H. pylori infection leads to the upregulation of anti-inflammatory molecules like IRAK-M and that IRAK-M has a direct impact on innate functions in DCs such as cytokine and costimulation molecule upregulation but may not affect T cell skewing.
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