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Ramadan HKA, Ahmed ZN, AboDief AR, Mohamed ZR, Hamed HM, El-Sherif TH. Human immunodeficiency virus and Helicobacter pylori coinfection: Immune modulation and eradication failure. Trop Doct 2025:494755251339521. [PMID: 40340469 DOI: 10.1177/00494755251339521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
The relationship between Human Immunodeficiency Virus (HIV) and Helicobacter pylori (H. pylori) is bidirectional and complex. Helicobacter pylori, by inducing local gastric and systemic immune responses, counteracts HIV invasion to CD4+ cells and other inflammatory cells and can reactivate HIV in latently infected immune cells. Human Immunodeficiency Virus infection, by reducing secretion of pro-inflammatory cytokines, reduces the incidence of H. pylori-induced gastric pathology. Gastric lymphoma regressed in some cases of people living with HIV (PLWH) after H. pylori eradication. Triple therapy for H. pylori could be associated with a strong immune. Treatment for both H. pylori and HIV can reduce the activation of either organism. However, the primary resistance to antibiotics such as levofloxacin, clarithromycin and metronidazole is higher among PLWH. This review highlights the need for further research and guidelines on the appropriate antibiotics in HIV-H. pylori co-infection particularly in PLWH who receive multiple antibiotic prophylaxis.
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Affiliation(s)
- Haidi Karam-Allah Ramadan
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Zeinab N Ahmed
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Abdel-Rahman AboDief
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Zeinab R Mohamed
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Hager M Hamed
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Taha H El-Sherif
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
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2
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Wang X, Zhao G, Shao S, Yao Y. Helicobacter pylori triggers inflammation and oncogenic transformation by perturbing the immune microenvironment. Biochim Biophys Acta Rev Cancer 2024; 1879:189139. [PMID: 38897421 DOI: 10.1016/j.bbcan.2024.189139] [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: 04/08/2024] [Revised: 06/09/2024] [Accepted: 06/14/2024] [Indexed: 06/21/2024]
Abstract
The immune microenvironment plays a critical regulatory role in the pathogenesis of Helicobacter pylori (H. pylori). Understanding the mechanisms that drive the transition from chronic inflammation to cancer may provide new insights for early detection of gastric cancer. Although chronic inflammation is frequent in precancerous gastric conditions, the monitoring function of the inflammatory microenvironment in the progression from H. pylori-induced chronic inflammation to gastric cancer remains unclear. This literature review summarizes significant findings on how H. pylori triggers inflammatory responses and facilitates cancer development through the immune microenvironment. Furthermore, the implications for future research and clinical applications are also addressed. The review is divided into four main sections: inflammatory response and immune evasion mechanisms induced by H. pylori, immune dysregulation associated with gastric cancer, therapeutic implications, and future perspectives on H. pylori-induced gastric carcinogenesis with a focus on the immune microenvironment.
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Affiliation(s)
- Xiuping Wang
- Department of Clinical Laboratory, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangsu, China
| | - Guang Zhao
- Department of Clinical Laboratory, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangsu, China; Department of Emergency Medicine, Kunshan Hospital Affiliated to Jiangsu University, Kunshan 215300, Jiangsu, China
| | - Shihe Shao
- School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China.
| | - Yongliang Yao
- Department of Clinical Laboratory, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangsu, China.
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3
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Fan J, Zhu J, Xu H. Strategies of Helicobacter pylori in evading host innate and adaptive immunity: insights and prospects for therapeutic targeting. Front Cell Infect Microbiol 2024; 14:1342913. [PMID: 38469348 PMCID: PMC10925771 DOI: 10.3389/fcimb.2024.1342913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/08/2024] [Indexed: 03/13/2024] Open
Abstract
Helicobacter pylori (H. pylori) is the predominant pathogen causing chronic gastric mucosal infections globally. During the period from 2011 to 2022, the global prevalence of H. pylori infection was estimated at 43.1%, while in China, it was slightly higher at approximately 44.2%. Persistent colonization by H. pylori can lead to gastritis, peptic ulcers, and malignancies such as mucosa-associated lymphoid tissue (MALT) lymphomas and gastric adenocarcinomas. Despite eliciting robust immune responses from the host, H. pylori thrives in the gastric mucosa by modulating host immunity, particularly by altering the functions of innate and adaptive immune cells, and dampening inflammatory responses adverse to its survival, posing challenges to clinical management. The interaction between H. pylori and host immune defenses is intricate, involving evasion of host recognition by modifying surface molecules, manipulating macrophage functionality, and modulating T cell responses to evade immune surveillance. This review analyzes the immunopathogenic and immune evasion mechanisms of H. pylori, underscoring the importance of identifying new therapeutic targets and developing effective treatment strategies, and discusses how the development of vaccines against H. pylori offers new hope for eradicating such infections.
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Affiliation(s)
- Jiawei Fan
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Jianshu Zhu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Hong Xu
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
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Brackman LC, Jung MS, Green EH, Joshi N, Revetta FL, McClain MS, Markham NO, Piazuelo MB, Scott Algood HM. IL-17 signaling protects against Helicobacter pylori-induced gastric cancer. Gut Microbes 2024; 16:2430421. [PMID: 39588838 PMCID: PMC11639209 DOI: 10.1080/19490976.2024.2430421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/19/2024] [Accepted: 11/12/2024] [Indexed: 11/27/2024] Open
Abstract
Helicobacter pylori infection is the predominant risk factor for the development of gastric cancer. Risk is enhanced by specific H. pylori virulence factors, diet, and the inflammatory response. Chronic activation of T helper (Th) 1 and Th17 pathways contributes to prolonged inflammation; yet, higher expression of IL-17 receptor (IL-17RA) is a favorable prognostic marker for survival after gastric cancer diagnosis. The protective impact of IL-17RA signaling is not understood. To investigate if IL-17RA signaling protects during H. pylori-induced carcinogenesis, the transgenic InsGAStg/tg mouse, which is prone to H. pylori-induced gastric cancer, was utilized. InsGAStg/tg mice and InsGAStg/tgIl17ra-/- mice were infected with a cag type 4 secretion system (T4SS) positive H. pylori strain for up to 6 months. Six weeks post-infection, IL-17RA deficiency led to increased bacterial burden, increased gastritis, and development of lymphoid follicles. Increased inflammation was associated with heightened cellular proliferation and earlier loss of parietal and chief cells in InsGAStg/tgIl17ra-/- mice. Gastric cancers developed more frequently by 3- and 6-months post-infection in H. pylori-infected InsGAStg/tgIl17ra-/- mice compared to InsGAStg/tg mice. Chronic inflammation was exacerbated with IL-17RA deficiency, characterized by elevated Th1/Th17 cytokines, increased B cell infiltration, and enhanced IgA production, despite reduced expression of the polymeric immunoglobulin receptor. Further, paragastric lymph nodes of InsGAStg/tgIl17ra-/- mice were enlarged relative to controls and displayed altered gene expression profiles. Increased inflammation was accompanied by a significant increase in Cybb expression, which encodes NADPH oxidase 2, suggesting that increased oxidative damage may occur in the absence of IL-17RA. Further, there is increased phosphorylation of histone 2AX in IL-17RA deficient mice, indicating that the DNA damage response is highly activated. These data suggest that IL-17RA signaling activates a protective pathway to prevent excessive inflammation which otherwise can lead to increased oxidative stress, DNA damage, and drive gastric carcinogenesis after H. pylori infection.
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Affiliation(s)
- Lee C. Brackman
- Department of Medicine, Division of Infectious Disease, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Matthew S. Jung
- Department of Medicine, Division of Infectious Disease, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Emily H. Green
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Institute of Infection, Immunity, and Inflammation (VI4), Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nikhita Joshi
- Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, USA
- School of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - Frank L. Revetta
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Mark S. McClain
- Department of Medicine, Division of Infectious Disease, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Institute of Infection, Immunity, and Inflammation (VI4), Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nicholas O. Markham
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Institute of Infection, Immunity, and Inflammation (VI4), Vanderbilt University Medical Center, Nashville, TN, USA
- Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, USA
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - M. Blanca Piazuelo
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Holly M. Scott Algood
- Department of Medicine, Division of Infectious Disease, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Institute of Infection, Immunity, and Inflammation (VI4), Vanderbilt University Medical Center, Nashville, TN, USA
- Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, USA
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5
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Fuchs S, Gong R, Gerhard M, Mejías-Luque R. Immune Biology and Persistence of Helicobacter pylori in Gastric Diseases. Curr Top Microbiol Immunol 2023; 444:83-115. [PMID: 38231216 DOI: 10.1007/978-3-031-47331-9_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
Helicobacter pylori is a prevalent pathogen, which affects more than 40% of the global population. It colonizes the human stomach and persists in its host for several decades or even a lifetime, if left untreated. The persistent infection has been linked to various gastric diseases, including gastritis, peptic ulcers, and an increased risk for gastric cancer. H. pylori infection triggers a strong immune response directed against the bacterium associated with the infiltration of innate phagocytotic immune cells and the induction of a Th1/Th17 response. Even though certain immune cells seem to be capable of controlling the infection, the host is unable to eliminate the bacteria as H. pylori has developed remarkable immune evasion strategies. The bacterium avoids its killing through innate recognition mechanisms and manipulates gastric epithelial cells and immune cells to support its persistence. This chapter focuses on the innate and adaptive immune response induced by H. pylori infection, and immune evasion strategies employed by the bacterium to enable persistent infection.
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Affiliation(s)
- Sonja Fuchs
- Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Department Preclinical Medicine, Technical University of Munich (TUM), Trogerstraße 30, 81675, Munich, Germany
| | - Ruolan Gong
- Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Department Preclinical Medicine, Technical University of Munich (TUM), Trogerstraße 30, 81675, Munich, Germany
| | - Markus Gerhard
- Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Department Preclinical Medicine, Technical University of Munich (TUM), Trogerstraße 30, 81675, Munich, Germany
| | - Raquel Mejías-Luque
- Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Department Preclinical Medicine, Technical University of Munich (TUM), Trogerstraße 30, 81675, Munich, Germany.
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Reyes VE. Helicobacter pylori Immune Response in Children Versus Adults. MEDICAL RESEARCH ARCHIVES 2022; 10:3370. [PMID: 37936946 PMCID: PMC10629867 DOI: 10.18103/mra.v10i12.3370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
H. pylori is perhaps the most prevalent human pathogen worldwide and infects almost half of the world's population. Despite the decreasing prevalence of infection overall, it is significant in developing countries. Most infections are acquired in childhood and persist for a lifetime unless treated. Children are often asymptomatic and often develop a tolerogenic immune response that includes T regulatory cells and their products, immunosuppressive cytokines, such as interleukin (IL)-10, and transforming growth factor-β (TGF-β). This contrasts to the gastric immune response seen in H. pylori-infected adults, where the response is mainly inflammatory, with predominant Th1 and Th17 cells, as well as, inflammatory cytokines, such as TNF-α, IFN-γ, IL-1, IL-6, IL-8, and IL-17. Therefore, compared to adults, infected children generally have limited gastric inflammation and peptic ulcer disease. H. pylori surreptitiously subverts immune defenses to persist in the human gastric mucosa for decades. The chronic infection might result in clinically significant diseases in adults, such as peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. This review compares the infection in children and adults and highlights the H. pylori virulence mechanisms responsible for the pathogenesis and immune evasion.
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Affiliation(s)
- Victor E. Reyes
- Department of Pediatrics, Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd. Galveston, TX 77555-0372 USA
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de Brito BB, Lemos FFB, Carneiro CDM, Viana AS, Barreto NMPV, Assis GADS, Braga BDC, Santos MLC, Silva FAFD, Marques HS, Silva NOE, de Melo FF. Immune response to Helicobacter pylori infection and gastric cancer development. World J Meta-Anal 2021; 9:257-276. [DOI: 10.13105/wjma.v9.i3.257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/24/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
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The Roles of IL-17, IL-21, and IL-23 in the Helicobacter pylori Infection and Gastrointestinal Inflammation: A Review. Toxins (Basel) 2021; 13:toxins13050315. [PMID: 33924897 PMCID: PMC8147029 DOI: 10.3390/toxins13050315] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/19/2021] [Accepted: 04/21/2021] [Indexed: 12/17/2022] Open
Abstract
Although millions of people have been infected by Helicobacter pylori (H. pylori), only a small proportion of infected individuals will develop adverse outcomes, ranging from chronic gastritis to gastric cancer. Advanced development of the disease has been well-linked with chronic inflammation, which is significantly impacted by the adaptive and humoral immunity response. From the perspective of cellular immunity, this review aims to clarify the intricate axis between IL-17, IL-21, and IL-23 in H. pylori-related diseases and the pathogenesis of inflammatory gastrointestinal diseases. CD4+ helper T (Th)-17 cells, with the hallmark pleiotropic cytokine IL-17, can affect antimicrobial activity and the pathogenic immune response in the gut environment. These circumstances cannot be separated, as the existence of affiliated cytokines, including IL-21 and IL-23, help maintain Th17 and accommodate humoral immune cells. Comprehensive understanding of the dynamic interaction between molecular host responses in H. pylori-related diseases and the inflammation process may facilitate further development of immune-based therapy.
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Altunöz D, Sayi Yazgan A. Helicobacter-stimulated IL-10-producing B cells suppress differentiation of lipopolysaccharide/Helicobacter felis-activated stimulatory dendritic cells. ACTA ACUST UNITED AC 2021; 45:214-224. [PMID: 33907502 PMCID: PMC8068769 DOI: 10.3906/biy-2012-11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/24/2021] [Indexed: 01/09/2023]
Abstract
Regulatory B cells (Bregs) produce antiinflammatory cytokines and inhibits proinflammatory response. Recently, immunosuppressive roles of Bregs in the effector functions of dendritic cells (DCs) were demonstrated. However, cross talk between Bregs and DCs in Helicobacter infection remains unknown. Here, we showed that direct stimulation of bone marrow-derived DCs (BM-DCs) with Helicobacter felis (H. felis) antigen upregulates their CD86 surface expression and causes the production of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), interleukin-12 (IL-12), and interleukin-10 (IL-10). Furthermore, prestimulation of DCs with supernatants derived from both Helicobacter-stimulated IL-10– B (Hfstim-IL-10– B) or IL-10+ B (Hfstim-IL-10+) cells suppresses the secretion of TNF-α and IL-6, but does not affect the expression of CD86 and secretion of IL-12 by lipopolysaccharide (LPS) or H. felis-activated BM-DCs. Remarkably, soluble factors secreted by Hfstim-IL-10– B cells, but not by Hfstim-IL-10+ B cells, suppress the secretion of IL-10 by BM-DCs upon subsequent LPS stimulation. In contrast, prestimulation with BM-DCs with supernatants of Hfstim-IL-10+ B cells before H. felis antigen stimulation induces significantly their IL-10 production. Collectively, our data indicated that prestimulation with soluble factors secreted by Hfstim-IL-10+ B cells, DCs exhibit a tolerogenic phenotype in response to LPS or Helicobacter antigen by secreting high levels of IL-10, but decreased levels of IL-6 and TNF-α.
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Affiliation(s)
- Doğuş Altunöz
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, İstanbul Technical University, İstanbul Turkey
| | - Ayça Sayi Yazgan
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, İstanbul Technical University, İstanbul Turkey
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Kononova S, Litvinova E, Vakhitov T, Skalinskaya M, Sitkin S. Acceptive Immunity: The Role of Fucosylated Glycans in Human Host-Microbiome Interactions. Int J Mol Sci 2021; 22:3854. [PMID: 33917768 PMCID: PMC8068183 DOI: 10.3390/ijms22083854] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/04/2021] [Accepted: 04/05/2021] [Indexed: 02/07/2023] Open
Abstract
The growth in the number of chronic non-communicable diseases in the second half of the past century and in the first two decades of the new century is largely due to the disruption of the relationship between the human body and its symbiotic microbiota, and not pathogens. The interaction of the human immune system with symbionts is not accompanied by inflammation, but is a physiological norm. This is achieved via microbiota control by the immune system through a complex balance of pro-inflammatory and suppressive responses, and only a disturbance of this balance can trigger pathophysiological mechanisms. This review discusses the establishment of homeostatic relationships during immune system development and intestinal bacterial colonization through the interaction of milk glycans, mucins, and secretory immunoglobulins. In particular, the role of fucose and fucosylated glycans in the mechanism of interactions between host epithelial and immune cells is discussed.
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Affiliation(s)
- Svetlana Kononova
- Department of Microbiology, State Research Institute of Highly Pure Biopreparations, 197110 St. Petersburg, Russia; (T.V.); (M.S.); (S.S.)
- Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Russia
| | - Ekaterina Litvinova
- Scientific-Research Institute of Neurosciences and Medicine, 630117 Novosibirsk, Russia;
- Siberian Federal Scientific Center of Agro-BioTechnologies, Russian Academy of Sciences, Krasnoobsk, 633501 Novosibirsk, Russia
| | - Timur Vakhitov
- Department of Microbiology, State Research Institute of Highly Pure Biopreparations, 197110 St. Petersburg, Russia; (T.V.); (M.S.); (S.S.)
| | - Maria Skalinskaya
- Department of Microbiology, State Research Institute of Highly Pure Biopreparations, 197110 St. Petersburg, Russia; (T.V.); (M.S.); (S.S.)
- Department of Internal Diseases, Gastroenterology and Dietetics, North-Western State Medical University Named after I.I. Mechnikov, 191015 St. Petersburg, Russia
| | - Stanislav Sitkin
- Department of Microbiology, State Research Institute of Highly Pure Biopreparations, 197110 St. Petersburg, Russia; (T.V.); (M.S.); (S.S.)
- Department of Internal Diseases, Gastroenterology and Dietetics, North-Western State Medical University Named after I.I. Mechnikov, 191015 St. Petersburg, Russia
- Institute of Perinatology and Pediatrics, Almazov National Medical Research Centre, 197341 St. Petersburg, Russia
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11
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Abdel-Moneim A, Abd El-Twab SM, Nabil A, El Kazafy SA. Effect of antidiabetic therapy on TNF-α, IL-18, IL-23 and IL-35 levels in T2DM patients with coincidental Helicobacter pylori infection. JOURNAL OF TAIBAH UNIVERSITY FOR SCIENCE 2020. [DOI: 10.1080/16583655.2020.1824669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Adel Abdel-Moneim
- Molecular Physiology Division, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Sanaa M. Abd El-Twab
- Molecular Physiology Division, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Ahmed Nabil
- Biotechnology Department, Postgraduate Studies for Advanced Science, Beni-Suef University, Beni-Suef, Egypt
| | - Salma A. El Kazafy
- Biotechnology Department, Postgraduate Studies for Advanced Science, Beni-Suef University, Beni-Suef, Egypt
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Azadegan-Dehkordi F, Abbasi A, Abadi ATB, Minooie K, Aslani P, Hosseini RS, Zandi F. From genes polymorphisms to mucosal expression of cytokines: evaluating IL-23/IL-17 axis in adult patients with gastritis. Afr Health Sci 2020; 20:1452-1462. [PMID: 33402994 PMCID: PMC7751554 DOI: 10.4314/ahs.v20i3.51] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background and Objective Chronic inflammation is the typical sign of gastritis that may shift into gastric cancer. IL-17A and IL-17F as a novel inflammatory cytokines subset of CD4+Th play the main role in inflammation. A key cytokine receptor in the inflammatory IL-17/IL-23 axis, the interleukin 23 receptor (IL23R), may be related to gastritis. We evaluated the correspondence between IL-17A G197A, IL-17F A7488G and IL23R+2199 A/C polymorphisms with TGF-β1, IL-6, IL-17, IL-21 and IL-23 mucosal mRNAs expression in uninfected H. Pylori (HP) chronic gastritis patients. Materials and Methods Total RNA and genomic DNA were separated from gastric biopsies of 44 patients with gastritis. Subsequently, mucosal mRNAs expression of TGF-β1, IL-6, IL-17, IL-21 and IL-23 were assessed by real-time PCR. To polymorphisms determination of IL-17A G197A, IL-17F A7488G and IL-23R +2199A/C the PCR-RFLP was used in gastric biopsies. Results Results point that IL-17A G197A, IL-17F A7488G and IL23R +2199A/C polymorphisms did not influence the mucosal expression of TGF-β1, IL-6, IL-17 and IL-21 (p> 0.05). In an opposite result, we don't find a correspondence between IL-17A G197A, IL-17F A7488G polymorphisms and mucosal expression of IL-23 (p> 0.05). In a contrary, we found a correlation between IL23R +2199A/C polymorphism and mucosal expression of IL-23 in patients with chronic gastritis (p< 0.05). Conclusion These findings propose that IL23R +2199A/C polymorphism may change the mucosal expression of IL-23 pattern in patients with gastritis disease in the absence of HP, but to support the conclusion, more research may be required.
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Affiliation(s)
| | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amin Talebi Bezmin Abadi
- Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Khaled Minooie
- Internist, Department of Internal Medicine, Medical Faculty, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Parya Aslani
- Kurdistan Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Razieh Sadat Hosseini
- Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Farid Zandi
- Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Meyer TF, Morey P. A Future for a Vaccine Against the Cancer-Inducing Bacterium Helicobacter pylori? MUCOSAL VACCINES 2020:579-596. [DOI: 10.1016/b978-0-12-811924-2.00033-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Blaser N, Backert S, Pachathundikandi SK. Immune Cell Signaling by Helicobacter pylori: Impact on Gastric Pathology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:77-106. [PMID: 31049845 DOI: 10.1007/5584_2019_360] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori represents a highly successful colonizer of the human stomach. Infections with this Gram-negative bacterium can persist lifelong, and although in the majority of cases colonization is asymptomatic, it can trigger pathologies ranging from chronic gastritis and peptic ulceration to gastric cancer. The interaction of the bacteria with the human host modulates immune responses in different ways to enable bacterial survival and persistence. H. pylori uses various pathogenicity-associated factors such as VacA, NapA, CGT, GGT, lipopolysaccharide, peptidoglycan, heptose 1,7-bisphosphate, ADP-heptose, cholesterol glucosides, urease and a type IV secretion system for controlling immune signaling and cellular functions. It appears that H. pylori manipulates multiple extracellular immune receptors such as integrin-β2 (CD18), EGFR, CD74, CD300E, DC-SIGN, MINCLE, TRPM2, T-cell and Toll-like receptors as well as a number of intracellular receptors including NLRP3, NOD1, NOD2, TIFA and ALPK1. Consequently, downstream signaling pathways are hijacked, inducing tolerogenic dendritic cells, inhibiting effector T cell responses and changing the gastrointestinal microbiota. Here, we discuss in detail the interplay of bacterial factors with multiple immuno-regulatory cells and summarize the main immune evasion and persistence strategies employed by H. pylori.
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Affiliation(s)
- Nicole Blaser
- Department of Biology, Institute for Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Steffen Backert
- Department of Biology, Institute for Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Suneesh Kumar Pachathundikandi
- Department of Biology, Institute for Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
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Abstract
Helicobacter pylori is a Gram-negative bacterium that infects the gastric epithelia of its human host. Everyone who is colonized with these pathogenic bacteria can develop gastric inflammation, termed gastritis. Additionally, a small proportion of colonized people develop more adverse outcomes, including gastric ulcer disease, gastric adenocarcinoma, or gastric mucosa-associated lymphoid tissue lymphoma. The development of these adverse outcomes is dependent on the establishment of a chronic inflammatory response. The development and control of this chronic inflammatory response are significantly impacted by CD4+ T helper cell activity. Noteworthy, T helper 17 (Th17) cells, a proinflammatory subset of CD4+ T cells, produce several proinflammatory cytokines that activate innate immune cell antimicrobial activity, drive a pathogenic immune response, regulate B cell responses, and participate in wound healing. Therefore, this review was written to take an intricate look at the involvement of Th17 cells and their affiliated cytokines (interleukin-17A [IL-17A], IL-17F, IL-21, IL-22, and IL-26) in regulating the immune response to H. pylori colonization and carcinogenesis.
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Milic L, Karamarkovic A, Popadic D, Sijacki A, Grigorov I, Milosevic E, Cuk V, Pesko P. Altered cytokine expression in Helicobacter pylori infected patients with bleeding duodenal ulcer. BMC Res Notes 2019; 12:278. [PMID: 31092295 PMCID: PMC6521506 DOI: 10.1186/s13104-019-4310-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 05/08/2019] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE Peptic ulcer disease is a condition in which an important role has infection with H. pylori. The most common complication of peptic ulcer is bleeding. The presence of H. pylori triggers local and systemic cytokine signaling which may affect processes such as healing, gastric or duodenal rupture, and carcinogenesis. In this study, we examined the concentrations of IL-1β, IL-6, IL-10, TNF, TGF-β and IL-17A in serum by enzyme immunoassay and their mRNA expressions in periulcer biopsies obtained from patients with bleeding peptic ulcer by means of real-time-PCR. RESULTS We have shown that pro-inflammatory IL-6 and TNF concentrations in serum were significantly higher in patients who were infected with H. pylori, while the concentrations of TGF-β and IL-17A were significantly lower compared to non-infected subjects. IL-17A expression in periulcer mucosa was significantly higher in patients who were infected with H. pylori, while the expression of other cytokines, there was no significant difference compared to non-infected controls. Considering higher serum concentrations in non-infected subjects and higher IL-17A expression in mucosal tissue of infected patients, our data support the studies that found IL-17A has protective role in eradication of H. pylori infection in infected patients.
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Affiliation(s)
- Ljiljana Milic
- Surgical Clinic “Nikola Spasić”, Zvezdara University Medical Center, Faculty of Medicine, University Belgrade, Dimitrija Tucovića 161, 11000 Belgrade, Serbia
| | - Aleksandar Karamarkovic
- Surgical Clinic “Nikola Spasić”, Zvezdara University Medical Center, Faculty of Medicine, University Belgrade, Dimitrija Tucovića 161, 11000 Belgrade, Serbia
| | - Dusan Popadic
- Institute of Microbiology and Immunology, Faculty of Medicine, University Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia
| | - Ana Sijacki
- Clinic for Emergency Surgery, Emergency Center, University Clinical Center of Serbia, Faculty of Medicine, University Belgrade, Visegradska 26, 11000 Belgrade, Serbia
| | - Ilijana Grigorov
- Department of Molecular Biology, Institute for Biological Research, Despota Stefana 142, 11000 Belgrade, Serbia
| | - Emina Milosevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia
| | - Vladica Cuk
- Surgical Clinic “Nikola Spasić”, Zvezdara University Medical Center, Faculty of Medicine, University Belgrade, Dimitrija Tucovića 161, 11000 Belgrade, Serbia
| | - Predrag Pesko
- Clinic for Digestive Surgery, University Clinical Center of Belgrade, Faculty of Medicine, University Belgrade, Koste Todorovica No6, 11000 Belgrade, Serbia
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Morey P, Meyer TF. The Sweeping Role of Cholesterol Depletion in the Persistence of Helicobacter pylori Infections. Curr Top Microbiol Immunol 2019; 421:209-227. [PMID: 31123891 DOI: 10.1007/978-3-030-15138-6_9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The ability of Helicobacter pylori to persist lifelong in the human gastric mucosa is a striking phenomenon. It is even more surprising since infection is typically associated with a vivid inflammatory response. Recent studies revealed the mechanism by which this pathogen inhibits the epithelial responses to IFN-γ and other central inflammatory cytokines in order to abolish an effective antimicrobial defense. The mechanism is based on the modification and depletion of cholesterol by the pathogen's cholesterol-α-glucosyltransferase. It abrogates the assembly of numerous cytokine receptors due to the reduction of lipid rafts. Particularly, the receptors for IFN-γ, IL-22, and IL-6 then fail to assemble properly and to activate JAK/STAT signaling. Consequently, cholesterol depletion prevents the release of antimicrobial peptides, including the highly effective β-defensin-3. Intriguingly, the inhibition is spatially restricted to heavily infected cells, while the surrounding epithelium continues to respond normally to cytokine stimulation, thus providing a platform of the intense inflammation typically observed in H. pylori infections. It appears that pathogen and host establish a homeostatic balance between tightly colonized and rather inflamed sites. This homeostasis is influenced by the levels of available cholesterol, which potentially exacerbate H. pylori-induced inflammation. The observed blockage of epithelial effector mechanisms by H. pylori constitutes a convincing explanation for the previous failures of T-cell-based vaccination against H. pylori, since infected epithelial cells remain inert upon stimulation by effector cytokines. Moreover, the mechanism provides a rationale for the carcinogenic action of this pathogen in that persistent infection and chronic inflammation represent a pro-carcinogenic environment. Thus, cholesterol-α-glucosyltransferase has been revealed as a central pathogenesis determinant of H. pylori.
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Affiliation(s)
- Pau Morey
- Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universidad de las Islas Baleares, Palma de Mallorca, Spain.
| | - Thomas F Meyer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
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Mechanisms of Inflammasome Signaling, microRNA Induction and Resolution of Inflammation by Helicobacter pylori. Curr Top Microbiol Immunol 2019; 421:267-302. [PMID: 31123893 DOI: 10.1007/978-3-030-15138-6_11] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammasome-controlled transcription and subsequent cleavage-mediated activation of mature IL-1β and IL-18 cytokines exemplify a crucial innate immune mechanism to combat intruding pathogens. Helicobacter pylori represents a predominant persistent infection in humans, affecting approximately half of the population worldwide, and is associated with the development of chronic gastritis, peptic ulcer disease, and gastric cancer. Studies in knockout mice have demonstrated that the pro-inflammatory cytokine IL-1β plays a central role in gastric tumorigenesis. Infection by H. pylori was recently reported to stimulate the inflammasome both in cells of the mouse and human immune systems. Using mouse models and in vitro cultured cell systems, the bacterial pathogenicity factors and molecular mechanisms of inflammasome activation have been analyzed. On the one hand, it appears that H. pylori-stimulated IL-1β production is triggered by engagement of the immune receptors TLR2 and NLRP3, and caspase-1. On the other hand, microRNA hsa-miR-223-3p is induced by the bacteria, which controls the expression of NLRP3. This regulating effect by H. pylori on microRNA expression was also described for more than 60 additionally identified microRNAs, indicating a prominent role for inflammatory and other responses. Besides TLR2, TLR9 becomes activated by H. pylori DNA and further TLR10 stimulated by the bacteria induce the secretion of IL-8 and TNF, respectively. Interestingly, TLR-dependent pathways can accelerate both pro- and anti-inflammatory responses during H. pylori infection. Balancing from a pro-inflammation to anti-inflammation phenotype results in a reduction in immune attack, allowing H. pylori to persistently colonize and to survive in the gastric niche. In this chapter, we will pinpoint the role of H. pylori in TLR- and NLRP3 inflammasome-dependent signaling together with the differential functions of pro- and anti-inflammatory cytokines. Moreover, the impact of microRNAs on H. pylori-host interaction will be discussed, and its role in resolution of infection versus chronic infection, as well as in gastric disease development.
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Morey P, Pfannkuch L, Pang E, Boccellato F, Sigal M, Imai-Matsushima A, Dyer V, Koch M, Mollenkopf HJ, Schlaermann P, Meyer TF. Helicobacter pylori Depletes Cholesterol in Gastric Glands to Prevent Interferon Gamma Signaling and Escape the Inflammatory Response. Gastroenterology 2018; 154:1391-1404.e9. [PMID: 29273450 DOI: 10.1053/j.gastro.2017.12.008] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 11/17/2017] [Accepted: 12/14/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Despite inducing an inflammatory response, Helicobacter pylori can persist in the gastric mucosa for decades. H pylori expression of cholesterol-α-glucosyltransferase (encoded by cgt) is required for gastric colonization and T-cell activation. We investigated how cgt affects gastric epithelial cells and the host immune response. METHODS MKN45 gastric epithelial cells, AGS cells, and human primary gastric epithelial cells (obtained from patients undergoing gastrectomy or sleeve resection or gastric antral organoids) were incubated with interferon gamma (IFNG) or interferon beta (IFNB) and exposed to H pylori, including cagPAI and cgt mutant strains. Some cells were incubated with methyl-β-cyclodextrin (to deplete cholesterol from membranes) or myriocin and zaragozic acid to prevent biosynthesis of sphingolipids and cholesterol and analyzed by immunoblot, immunofluorescence, and reverse transcription quantitative polymerase chain reaction analyses. We compared gene expression patterns among primary human gastric cells, uninfected or infected with H pylori P12 wt or P12Δcgt, using microarray analysis. Mice with disruption of the IFNG receptor 1 (Ifngr1-/- mice) and C57BL6 (control) mice were infected with PMSS1 (wild-type) or PMSS1Δcgt H pylori; gastric tissues were collected and analyzed by reverse transcription quantitative polymerase chain reaction or confocal microscopy. RESULTS In primary gastric cells and cell lines, infection with H pylori, but not cgt mutants, blocked IFNG-induced signaling via JAK and STAT. Cells infected with H pylori were depleted of cholesterol, which reduced IFNG signaling by disrupting lipid rafts, leading to reduced phosphorylation (activation) of JAK and STAT1. H pylori infection of cells also blocked signaling by IFNB, interleukin 6 (IL6), and IL22 and reduced activation of genes regulated by these signaling pathways, including cytokines that regulate T-cell function (MIG and IP10) and anti-microbial peptides such as human β-defensin 3 (hBD3). We found that this mechanism allows H pylori to persist in proximity to infected cells while inducing inflammation only in the neighboring, non-infected epithelium. Stomach tissues from mice infected with PMSS1 had increased levels of IFNG, but did not express higher levels of interferon-response genes. Expression of the IFNG-response gene IRF1 was substantially higher in PMSS1Δcgt-infected mice than PMSS1-infected mice. Ifngr1-/- mice were colonized by PMSS1 to a greater extent than control mice. CONCLUSIONS H pylori expression of cgt reduces cholesterol levels in infected gastric epithelial cells and thereby blocks IFNG signaling, allowing the bacteria to escape the host inflammatory response. These findings provide insight into the mechanisms by which H pylori might promote gastric carcinogenesis (persisting despite constant inflammation) and ineffectiveness of T-cell-based vaccines against H pylori.
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Affiliation(s)
- Pau Morey
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Lennart Pfannkuch
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Ervinna Pang
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Francesco Boccellato
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Michael Sigal
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany; Department of Hepatology and Gastroenterology, Charité University Medicine, Berlin, Germany
| | - Aki Imai-Matsushima
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Victoria Dyer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Manuel Koch
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Hans-Joachim Mollenkopf
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Philipp Schlaermann
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Thomas F Meyer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
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20
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Proinflammatory Cytokine IL-17 Shows a Significant Association with Helicobacter pylori Infection and Disease Severity. Gastroenterol Res Pract 2017; 2017:6265150. [PMID: 29391865 PMCID: PMC5748147 DOI: 10.1155/2017/6265150] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 10/11/2017] [Accepted: 10/29/2017] [Indexed: 01/18/2023] Open
Abstract
Background The pro- and anti-inflammatory cytokines play an important role in the immune response against H. pylori infection. The proinflammatory cytokines of Th17 cells have been suggested to play a major role in H. pylori infection and resulting gastric inflammation. Objective The objective of this study was to compare the expression of selected inflammatory cytokines (IL-10, IL-17, IL-21, IL-23, and TNF-α) in H. pylori-infected patients and healthy controls and to understand their association with H. pylori infection and disease severity. Results The expression levels of IL-17 and IL-23 were significantly higher in H. pylori-infected patients. The expression of IL-21 was also higher in H. pylori-positive patients but there was no significant association with infection. IL-17 expression showed a significant increase with the severity of chronic gastritis. Conclusion The proinflammatory cytokine, IL-17, shows a significant association with H. pylori infection and disease severity in a Sri Lankan dyspeptic patient population.
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Dixon BREA, Radin JN, Piazuelo MB, Contreras DC, Algood HMS. IL-17a and IL-22 Induce Expression of Antimicrobials in Gastrointestinal Epithelial Cells and May Contribute to Epithelial Cell Defense against Helicobacter pylori. PLoS One 2016; 11:e0148514. [PMID: 26867135 PMCID: PMC4750979 DOI: 10.1371/journal.pone.0148514] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 01/19/2016] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori colonization of the human stomach can lead to adverse clinical outcomes including gastritis, peptic ulcers, or gastric cancer. Current data suggest that in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization. Specifically, CD4+ T cell responses impact the pathology elicited in response to H. pylori. Because gastritis is believed to be the initiating host response to more detrimental pathological outcomes, there has been a significant interest in pro-inflammatory T cell cytokines, including the cytokines produced by T helper 17 cells. Th17 cells produce IL-17A, IL-17F, IL-21 and IL-22. While these cytokines have been linked to inflammation, IL-17A and IL-22 are also associated with anti-microbial responses and control of bacterial colonization. The goal of this research was to determine the role of IL-22 in activation of antimicrobial responses in models of H. pylori infection using human gastric epithelial cell lines and the mouse model of H. pylori infection. Our data indicate that IL-17A and IL-22 work synergistically to induce antimicrobials and chemokines such as IL-8, components of calprotectin (CP), lipocalin (LCN) and some β-defensins in both human and primary mouse gastric epithelial cells (GEC) and gastroids. Moreover, IL-22 and IL-17A-activated GECs were capable of inhibiting growth of H. pylori in vitro. While antimicrobials were activated by IL-17A and IL-22 in vitro, using a mouse model of H. pylori infection, the data herein indicate that IL-22 deficiency alone does not render mice more susceptible to infection, change their antimicrobial gene transcription, or significantly change their inflammatory response.
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Affiliation(s)
- Beverly R. E. A. Dixon
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Jana N. Radin
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
| | - M. Blanca Piazuelo
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Diana C. Contreras
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Holly M. Scott Algood
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America
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22
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Xiong LJ, Mao M. Current views of the relationship between Helicobacter pylori and Henoch-Schonlein purpura in children. World J Clin Pediatr 2016; 5:82-88. [PMID: 26862506 PMCID: PMC4737697 DOI: 10.5409/wjcp.v5.i1.82] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 11/09/2015] [Accepted: 11/17/2015] [Indexed: 02/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) is one of the factors involved in the pathogenesis of various gastrointestinal diseases and may play a potential role in certain extra-intestinal diseases. H. pylori infection are mainly acquired during childhood, and it has been reported that in endemic areas of China the infection rates are extraordinarily higher in HSP children, particular those with abdominal manifestations. Furthermore, eradication therapy may ameliorate Henoch-Schonlein purpura (HSP) manifestations and decrease the recurrence of HSP. Therefore, results suggested that detection of H. pylori infection by appropriate method ought to be applied in HSP children. Current evidences indicate that local injury of gastric mucosa and immunological events induced by H. pylori infection are involved in the development of HSP. Increased serum IgA, cryoglobulins, C3 levels, autoimmunity, proinflammatory substances and molecular mimicry inducing immune complex and cross-reactive antibodies caused by H. pylori infection might play their roles in the course of HSP. However, there are no investigations confirming the causality between H. pylori infection and HSP, and the pathogenesis mechanism is still unclear. More bench and clinical studies need to be executed to elaborate the complex association between H. pylori and HSP.
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23
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Helicobacter pylori Resists the Antimicrobial Activity of Calprotectin via Lipid A Modification and Associated Biofilm Formation. mBio 2015; 6:e01349-15. [PMID: 26646009 PMCID: PMC4669380 DOI: 10.1128/mbio.01349-15] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Helicobacter pylori is one of several pathogens that persist within the host despite a robust immune response. H. pylori elicits a proinflammatory response from host epithelia, resulting in the recruitment of immune cells which manifests as gastritis. Relatively little is known about how H. pylori survives antimicrobials, including calprotectin (CP), which is present during the inflammatory response. The data presented here suggest that one way H. pylori survives the nutrient sequestration by CP is through alteration of its outer membrane. CP-treated H. pylori demonstrates increased bacterial fitness in response to further coculture with CP. Moreover, CP-treated H. pylori cultures form biofilms and demonstrate decreased cell surface hydrophobicity. In response to CP, the H. pylori Lpx lipid A biosynthetic enzymes are not fully functional. The lipid A molecules observed in H. pylori cultures treated with CP indicate that the LpxF, LpxL, and LpxR enzyme functions are perturbed. Transcriptional analysis of lpxF, lpxL, and lpxR indicates that metal restriction by CP does not control this pathway through transcriptional regulation. Analyses of H. pylori lpx mutants reveal that loss of LpxF and LpxL results in increased fitness, similar to what is observed in the presence of CP; moreover, these mutants have significantly increased biofilm formation and reduced cell surface hydrophobicity. Taken together, these results demonstrate a novel mechanism of H. pylori resistance to the antimicrobial activity of CP via lipid A modification strategies and resulting biofilm formation. Helicobacter pylori evades recognition of the host’s immune system by modifying the lipid A component of lipopolysaccharide. These results demonstrate for the first time that the lipid A modification pathway is influenced by the host’s nutritional immune response. H. pylori’s exposure to the host Mn- and Zn-binding protein calprotectin perturbs the function of 3 enzymes involved in the lipid A modification pathway. Moreover, CP treatment of H. pylori, or mutants with an altered lipid A, exhibit increased bacterial fitness and increased biofilm formation. This suggests that H. pylori modifies its cell surface structure to survive under the stress imposed by the host immune response. These results provide new insights into the molecular mechanisms that influence the biofilm lifestyle and how endotoxin modification, which renders H. pylori resistant to cationic antimicrobial peptides, can be inactivated in response to sequestration of nutrient metals.
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Menheniott TR, Judd LM, Giraud AS. STAT3: a critical component in the response to Helicobacter pylori infection. Cell Microbiol 2015; 17:1570-82. [PMID: 26332850 DOI: 10.1111/cmi.12518] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 08/16/2015] [Accepted: 08/28/2015] [Indexed: 12/15/2022]
Abstract
STAT3 imparts a profound influence on both the epithelial and immune components of the gastric mucosa, and through regulation of key intracellular signal transduction events, is well placed to control inflammatory and oncogenic outcomes in the context of Helicobacter (H.) pylori infection. Here we review the roles of STAT3 in the host immune response to H. pylori infection, from both gastric mucosal and systemic perspectives, as well as alluding more specifically to STAT3-dependent mechanisms that might be exploited as drug targets.
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Affiliation(s)
- Trevelyan R Menheniott
- Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
| | - Louise M Judd
- Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
| | - Andrew S Giraud
- Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
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25
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26
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Oghumu S, Satoskar A. The emerging role of dendritic cells in the host immune response against Helicobacter pylori. Front Microbiol 2014; 5:560. [PMID: 25386172 PMCID: PMC4208416 DOI: 10.3389/fmicb.2014.00560] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 10/06/2014] [Indexed: 12/30/2022] Open
Affiliation(s)
- Steve Oghumu
- Department of Pathology, Ohio State University Medical Center Columbus, OH, USA ; Department of Oral Biology, Ohio State University College of Dentistry Columbus, OH, USA
| | - Abhay Satoskar
- Department of Pathology, Ohio State University Medical Center Columbus, OH, USA
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27
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Gaddy JA, Radin JN, Loh JT, Piazuelo MB, Kehl-Fie TE, Delgado AG, Ilca FT, Peek RM, Cover TL, Chazin WJ, Skaar EP, Scott Algood HM. The host protein calprotectin modulates the Helicobacter pylori cag type IV secretion system via zinc sequestration. PLoS Pathog 2014; 10:e1004450. [PMID: 25330071 PMCID: PMC4199781 DOI: 10.1371/journal.ppat.1004450] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 09/04/2014] [Indexed: 12/11/2022] Open
Abstract
Transition metals are necessary for all forms of life including microorganisms, evidenced by the fact that 30% of all proteins are predicted to interact with a metal cofactor. Through a process termed nutritional immunity, the host actively sequesters essential nutrient metals away from invading pathogenic bacteria. Neutrophils participate in this process by producing several metal chelating proteins, including lactoferrin and calprotectin (CP). As neutrophils are an important component of the inflammatory response directed against the bacterium Helicobacter pylori, a major risk factor for gastric cancer, it was hypothesized that CP plays a role in the host response to H. pylori. Utilizing a murine model of H. pylori infection and gastric epithelial cell co-cultures, the role CP plays in modifying H. pylori -host interactions and the function of the cag Type IV Secretion System (cag T4SS) was investigated. This study indicates elevated gastric levels of CP are associated with the infiltration of neutrophils to the H. pylori-infected tissue. When infected with an H. pylori strain harboring a functional cag T4SS, calprotectin-deficient mice exhibited decreased bacterial burdens and a trend toward increased cag T4SS -dependent inflammation compared to wild-type mice. In vitro data demonstrate that culturing H. pylori with sub-inhibitory doses of CP reduces the activity of the cag T4SS and the biogenesis of cag T4SS-associated pili in a zinc-dependent fashion. Taken together, these data indicate that zinc homeostasis plays a role in regulating the proinflammatory activity of the cag T4SS.
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Affiliation(s)
- Jennifer A. Gaddy
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Jana N. Radin
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - John T. Loh
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - M. Blanca Piazuelo
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Thomas E. Kehl-Fie
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Alberto G. Delgado
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Florin T. Ilca
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Richard M. Peek
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Timothy L. Cover
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Walter J. Chazin
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Eric P. Skaar
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Holly M. Scott Algood
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- * E-mail:
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28
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Carbo A, Olivares-Villagómez D, Hontecillas R, Bassaganya-Riera J, Chaturvedi R, Piazuelo MB, Delgado A, Washington MK, Wilson KT, Algood HMS. Systems modeling of the role of interleukin-21 in the maintenance of effector CD4+ T cell responses during chronic Helicobacter pylori infection. mBio 2014; 5:e01243-14. [PMID: 25053783 PMCID: PMC4120195 DOI: 10.1128/mbio.01243-14] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 06/25/2014] [Indexed: 01/25/2023] Open
Abstract
The development of gastritis during Helicobacter pylori infection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa during H. pylori infection, we combined mathematical modeling of CD4(+) T cell differentiation with in vivo mechanistic studies. We infected IL-21-deficient and wild-type mice with H. pylori strain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. Chronically H. pylori-infected IL-21-deficient mice had higher H. pylori colonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. These in vivo data were used to calibrate an H. pylori infection-dependent, CD4(+) T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronic H. pylori infection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4(+) splenocyte-specific tbx21 and rorc expression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4(+) T cell-specific IL-10 expression in H. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronic H. pylori infection in a STAT1- and STAT3-dependent manner, therefore playing a major role controlling H. pylori infection and gastritis. Importance: Helicobacter pylori is the dominant member of the gastric microbiota in more than 50% of the world's population. H. pylori colonization has been implicated in gastritis and gastric cancer, as infection with H. pylori is the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis during H. pylori infection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized with H. pylori as an alternative to aggressive antibiotics.
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Affiliation(s)
| | - Danyvid Olivares-Villagómez
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | | | | | - Rupesh Chaturvedi
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - M Blanca Piazuelo
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Alberto Delgado
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - M Kay Washington
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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Zawahir S, Czinn SJ, Nedrud JG, Blanchard TG. Vaccinating against Helicobacter pylori in the developing world. Gut Microbes 2013; 4:568-76. [PMID: 24253617 PMCID: PMC3928166 DOI: 10.4161/gmic.27093] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [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 infects more than half the world's population and in developing nations the incidence can be over 90%. The morbidity and mortality associated with H. pylori-associated diseases including ulcers and gastric cancer therefore, disproportionately impact the developing world. Mice have been used extensively to demonstrate the feasibility of developing a vaccine for H. pylori infection, and for testing antigens, routes of immunization, dose, and adjuvants. These successes however, have not translated well in clinical trials. Although there are examples where immune responses have been activated, there are few instances of achieving a reduced bacterial load. In vivo and in vitro analyses in both mice and humans demonstrates that the host responds to H. pylori infection through the activation of immunoregulatory mechanisms designed to suppress the anti-H. pylori response. Improved vaccine efficacy therefore, will require the inclusion of factors that over-ride or re-program these immunoregulatory rersponse mechanisms.
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Affiliation(s)
- Shamila Zawahir
- Department of Pediatrics; University of Maryland School of Medicine; Baltimore, MD USA
| | - Steven J Czinn
- Department of Pediatrics; University of Maryland School of Medicine; Baltimore, MD USA
| | - John G Nedrud
- Department of Pathology; Case Western Reserve University School of Medicine; Cleveland, OH USA
| | - Thomas G Blanchard
- Department of Pediatrics; University of Maryland School of Medicine; Baltimore, MD USA,Correspondence to: Thomas G Blanchard,
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Abstract
Over the last decades, it has become evident that chronic infection by Helicobacter pylori is achieved by colonizing an almost exclusive niche and hiding from many of the host's cellular immune defense mechanisms. Although recent years have seen progress in our understanding of the innate and adaptive immune response against H. pylori, it is still uncertain how to promote the development of immunity with the final goal of a successful vaccine. Research published in the last year revealed an intriguing mutual regulation of innate response mechanisms of mucosal epithelial cells by the host and H. pylori, respectively. A further focus was put on the interaction between H. pylori and dendritic cells, with some emphasis on the inflammasome and the resulting T-cell responses. Moreover, the function of microRNAs in macrophages and gastric MALT lymphoma development has been studied in more detail. Several novel antigens and adjuvants have been tested as vaccination strategies, primarily in mice. In this review, we present a concise summary of advances in the area of inflammation, immunity, and vaccines during the last twelve months.
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Affiliation(s)
- Manuel Koch
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
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Lina TT, Pinchuk IV, House J, Yamaoka Y, Graham DY, Beswick EJ, Reyes VE. CagA-dependent downregulation of B7-H2 expression on gastric mucosa and inhibition of Th17 responses during Helicobacter pylori infection. THE JOURNAL OF IMMUNOLOGY 2013; 191:3838-46. [PMID: 23997227 DOI: 10.4049/jimmunol.1300524] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Gastric epithelial cells (GECs) are the primary target for Helicobacter pylori infection and may act as APCs regulating local T cell responses. We previously reported that H. pylori infection of GECs induces the expression of the T cell coinhibitory molecule B7-H1 on GECs. This process contributes to the hyporesponsiveness of CD4(+) effector T cells and accumulation of regulatory T cells. In the present study, we investigated the impact of H. pylori cytotoxin-associated gene A (CagA) on the modulation of the expression of the T cell costimulator B7-H2 by GECs. B7-H2 is involved in promoting Th17 type responses. H. pylori infection downregulates B7-H2 expression by GECs in a CagA-dependent manner. IFN-γ, which is increased in the H. pylori-infected gastric mucosa, synergizes with H. pylori in downregulating B7-H2 expression by GECs. CagA-mediated modulation of B7-H2 on GECs involves p70 S6 kinase phosphorylation. The CagA-dependent B7-H2 downregulation in GECs correlates with a decrease in Th17 type responses in vitro and in vivo. Furthermore, CagA-dependent modulation of Th17 responses was inversely correlated with the H. pylori colonization levels in vivo. Our data suggest that CagA contributes to the ability of H. pylori to evade Th17-mediated clearance by modulating expression of B7-H2 and, thus, to the establishment of the H. pylori chronic infection.
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Affiliation(s)
- Taslima T Lina
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555
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Hocès de la Guardia A, Staedel C, Kaafarany I, Clément A, Roubaud Baudron C, Mégraud F, Lehours P. Inflammatory cytokine and microRNA responses of primary human dendritic cells cultured with Helicobacter pylori strains. Front Microbiol 2013; 4:236. [PMID: 23970881 PMCID: PMC3747313 DOI: 10.3389/fmicb.2013.00236] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 07/30/2013] [Indexed: 12/31/2022] Open
Abstract
Primary human dendritic cells (DC) were used to explore the inflammatory effectors, including cytokines and microRNAs, regulated by Helicobacter pylori. In a 48 h ex-vivo co-culture system, both H. pylori B38 and B45 strains activated human DCs and promoted a strong inflammatory response characterized by the early production of pro-inflammatory TNFα and IL-6 cytokines, followed by IL-10, IL-1β, and IL-23 secretion. IL-23 was the only cytokine dependent on the cag pathogenicity island status of the bacterial strains. DC activation and cytokine production were accompanied by an early miR-146a upregulation followed by a strong miR-155 induction, which mainly controlled TNFα production. These results pave the way for further investigations into the nature of H. pylori antigens and the subsequently activated signaling pathways involved in the inflammatory response to H. pylori infection, the deregulation of which may likely contribute to gastric lymphomagenesis.
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Affiliation(s)
- Anaïs Hocès de la Guardia
- Bacteriology Laboratory, Université Bordeaux Bordeaux, France ; Institut National de la Santé et de la Recherche Médicale, U853 Bordeaux, France
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Ding H, Nedrud JG, Blanchard TG, Zagorski BM, Li G, Shiu J, Xu J, Czinn SJ. Th1-mediated immunity against Helicobacter pylori can compensate for lack of Th17 cells and can protect mice in the absence of immunization. PLoS One 2013; 8:e69384. [PMID: 23874957 PMCID: PMC3708891 DOI: 10.1371/journal.pone.0069384] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2013] [Accepted: 06/09/2013] [Indexed: 12/29/2022] Open
Abstract
Helicobacter pylori (H. pylori) infection can be significantly reduced by immunization in mice. Th17 cells play an essential role in the protective immune response. Th1 immunity has also been demonstrated to play a role in the protective immune response and can compensate in the absence of IL-17. To further address the potential of Th1 immunity, we investigated the efficacy of immunization in mice deficient in IL-23p19, a cytokine that promotes Th17 cell development. We also examined the course of Helicobacter infection in unimmunized mice treated with Th1 promoting cytokine IL-12. C57BL/6, IL-12 p35 KO, and IL-23 p19 KO mice were immunized and challenged with H. pylori. Protective immunity was evaluated by CFU determination and QPCR on gastric biopsies. Gastric and splenic IL-17 and IFNγ levels were determined by PCR or by ELISA. Balb/c mice were infected with H. felis and treated with IL-12 therapy and the resulting gastric bacterial load and inflammatory response were assessed by histologic evaluation. Vaccine induced reductions in bacterial load that were comparable to wild type mice were observed in both IL-12 p35 and IL-23 p19 KO mice. In the absence of IL-23 p19, IL-17 levels remained low but IFNγ levels increased significantly in both immunized challenged and unimmunized/challenged mice. Additionally, treatment of H. felis-infected Balb/c mice with IL-12 resulted in increased gastric inflammation and the eradication of bacteria in most mice. These data suggest that Th1 immunity can compensate for the lack of IL-23 mediated Th17 responses, and that protective Th1 immunity can be induced in the absence of immunization through cytokine therapy of the infected host.
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Affiliation(s)
- Hua Ding
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - John G. Nedrud
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, Ohio, United States of America
| | - Thomas G. Blanchard
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | | | - Guanghui Li
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Jessica Shiu
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Jinghua Xu
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Steven J. Czinn
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
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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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Horvath DJ, Radin JN, Cho SH, Washington MK, Algood HMS. The interleukin-17 receptor B subunit is essential for the Th2 response to Helicobacter pylori, but not for control of bacterial burden. PLoS One 2013; 8:e60363. [PMID: 23533678 PMCID: PMC3606319 DOI: 10.1371/journal.pone.0060363] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 02/26/2013] [Indexed: 12/30/2022] Open
Abstract
Helicobacter pylori infection leads to an inflammatory response in 100% of infected individuals. The inflammatory cells which are recruited to the gastric mucosa during infection produce several pro- and anti-inflammatory cytokines including several cytokines in the interleukin-17 family. The anti-inflammatory cytokine, interleukin 25 (IL-25, also known as IL-17E), signals through a receptor, which is a heterotrimeric receptor comprised of two IL-17 receptor A subunits and an IL-17 receptor B subunit. Previous studies in our laboratory demonstrated that IL-17RA is required to control infection with Helicobacter pylori in the mouse model. Moreover, the absence of IL-17 receptor A leads to a significant B cell infiltrate and a remarkable increase in lymphoid follicle formation in response to infection compared to infection in wild-type mice. We hypothesized that IL-25, which requires both IL-17 receptor A and IL-17 receptor B for signaling, may play a role in control of inflammation in the mouse model of Helicobacter pylori infection. IL-17 receptor B deficient mice, IL-17 receptor A deficient mice and wild-type mice were infected with Helicobacter pylori (strains SS1 and PMSS1). At several time points H. pylori-infected mice were sacrificed to investigate their ability to control infection and inflammation. Moreover, the effects of IL-17 receptor B deficiency on T helper cytokine expression and H. pylori- specific serum antibody responses were measured. IL-17 receptor B-/- mice (unlike IL-17 receptor A-/- mice) exhibited similar or modest changes in gastric colonization, inflammation, and Th1 and Th17 helper cytokine responses to wild-type mice infected with Helicobacter pylori. However, H. pylori-infected IL-17 receptor B-/- mice have reduced expression of IL-4 and lower serum IgG1 and IgG2a levels compared to infected IL-17 receptor A-/- and wild-type mice. These data indicate that signaling through the IL-17 receptor B subunit is not necessary for control of Helicobacter pylori in our model.
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Affiliation(s)
- Dennis J. Horvath
- Departments of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Jana N. Radin
- Departments of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Sung Hoon Cho
- Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - M. Kay Washington
- Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Holly M. Scott Algood
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America
- Departments of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- * E-mail:
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Abstract
Half of the world's population is infected with Helicobacter pylori and approximately 20% of infected individuals develop overt clinical disease such as ulcers and stomach cancer. Paradoxically, despite its classification as a class I carcinogen, H. pylori has been shown to be protective against development of asthma, allergy, and esophageal disease. Given these conflicting roles for H. pylori, researchers are attempting to define the environmental, host, and pathogen interactions that ultimately result in severe disease in some individuals. From the bacterial perspective, the toxins, CagA and VacA, have each been shown to be polymorphic and to contribute to disease in an allele-dependent manner. Based on the notable advances that have recently been made in the CagA field, herein we review recent studies that have begun to shed light on the role of CagA polymorphism in H. pylori disease. Moreover, we discuss the potential interaction of CagA and VacA as a mediator of gastric disease.
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Hitzler I, Kohler E, Engler DB, Yazgan AS, Müller A. The role of Th cell subsets in the control of Helicobacter infections and in T cell-driven gastric immunopathology. Front Immunol 2012; 3:142. [PMID: 22675328 PMCID: PMC3365484 DOI: 10.3389/fimmu.2012.00142] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 05/16/2012] [Indexed: 12/12/2022] Open
Abstract
Chronic infection with the gastric bacterial pathogen Helicobacter pylori causes gastric adenocarcinoma in a particularly susceptible fraction of the infected population. The intestinal type of gastric cancer is preceded by a series of preneoplastic lesions that are of immunopathological origin, and that can be recapitulated by experimental infection of C57BL/6 mice with Helicobacter species. Several lines of evidence suggest that specific T cell subsets and/or their signature cytokines contribute to the control of Helicobacter infections on the one hand, and to the associated gastric preneoplastic pathology on the other. Here, we have used virulent H. pylori and H. felis isolates to infect mice that lack α/β T cells due to a targeted deletion of the T cell receptor β-chain, or are deficient for the unique p35 and p19 subunits of the Th1- and Th17-polarizing cytokines interleukin (IL)-12 and IL-23, respectively. We found that α/β T cells are absolutely required for Helicobacter control and for the induction of gastric preneoplastic pathology. In contrast, neither IL-12-dependent Th1 nor IL-23-dependent Th17 cells were essential for controlling the infection; IL-12p35-/- and IL-23p19-/- mice did not differ significantly from wild type animals with respect to Helicobacter colonization densities. Gastritis and gastric preneoplastic pathology developed to a similar extent in all three strains upon H. felis infection; in the H. pylori infection model, IL-23p19-/- mice exhibited significantly less gastritis and precancerous pathology. In summary, the results indicate that neither Th1 nor Th17 cells are by themselves essential for Helicobacter control; the associated gastric pathology is reduced only in the absence of Th17-polarizing IL-23, and only in the H. pylori, but not the H. felis infection model. The results thus suggest the involvement of other, as yet unknown T cell subsets in both processes.
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Affiliation(s)
- Iris Hitzler
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
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