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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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Zhang F, Chen J, Zhang Z, Wu J, Qu Y, Ni L, Zhang G, Liu K, Guo L. M cells targeted H. pylori antigen SAM-FAdE displayed on bacterium-like particles induce protective immunity. J Nanobiotechnology 2025; 23:23. [PMID: 39825347 PMCID: PMC11748607 DOI: 10.1186/s12951-025-03111-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 01/11/2025] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori), a specific bacterium capable of surviving in the acidic environment of the stomach, has been recognized as a group of causative agents of gastric cancer. Therefore, the development of mucosal vaccines against H. pylori is expected to provide an important direction for the treatment of chronic gastritis and the prevention of gastric cancer. METHODS AND RESULTS In this study, we used bacteria-like particles (BLPs) obtained by treating Lactic acid bacteria (L. lactis) with hot acid, and successfully displayed the M cell-targeted H. pylori multi-epitope purified antigen SAM-FAdE, with 90% display efficiency. In addition, BLPs-SAM-FAdE can effectively target M cell models and M cells of mouse Peyer's patches (PPs) through oral immunization, promote the transport of particulate vaccines to dendritic cells (BMDCs) and stimulate their maturation, significantly increased proportion of plasma cells and germinal centers B cells. This indicates that the vaccination can induce notable antigen-specific mucosal immune responses (production of sIgA), CD4+ T cell responses (Th1/Th2/Th17) and humoral immune responses (production of serum IgG). Furthermore, oral BLPs-SAM-FAdE dramatically reduced the H. pylori adhesion and specific 16S rRNA expression of H. pylori in gastric mucosal tissue, protecting gastric tissue from damage. CONCLUSION BLPs-SAM-FAdE can significantly reduce the adhesion of H. pylori in gastric mucosal tissue and inhibit gastritis and gastric damage caused by H. pylori infection.
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Affiliation(s)
- Furui Zhang
- School of First Clinical Medical, Ningxia Medical University, Yinchuan, 750004, China
- School of Laboratory, Ningxia Medical University, Yinchuan, 750004, China
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Jiale Chen
- School of First Clinical Medical, Ningxia Medical University, Yinchuan, 750004, China
| | - Zhen Zhang
- Department of Geriatrics and Special Needs Medicine, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Jing Wu
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Yuliang Qu
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Linhan Ni
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China
| | - Guolin Zhang
- Suzhou Institute for Drug Control, Suzhou, China
| | - Kunmei Liu
- Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China.
| | - Le Guo
- School of First Clinical Medical, Ningxia Medical University, Yinchuan, 750004, China.
- School of Laboratory, Ningxia Medical University, Yinchuan, 750004, China.
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China.
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3
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Elbehiry A, Marzouk E, Abalkhail A, Sindi W, Alzahrani Y, Alhifani S, Alshehri T, Anajirih NA, ALMutairi T, Alsaedi A, Alzaben F, Alqrni A, Draz A, Almuzaini AM, Aljarallah SN, Almujaidel A, Abu-Okail A. Pivotal role of Helicobacter pylori virulence genes in pathogenicity and vaccine development. Front Med (Lausanne) 2025; 11:1523991. [PMID: 39850097 PMCID: PMC11756510 DOI: 10.3389/fmed.2024.1523991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 12/13/2024] [Indexed: 01/25/2025] Open
Abstract
One of the most prevalent human infections is Helicobacter pylori (H. pylori), which affects more than half of the global population. Although H. pylori infections are widespread, only a minority of individuals develop severe gastroduodenal disorders. The global resistance of H. pylori to antibiotics has reached concerning levels, significantly impacting the effectiveness of treatment. Consequently, the development of vaccines targeting virulence factors may present a viable alternative for the treatment and prevention of H. pylori infections. This review aims to provide a comprehensive overview of the current understanding of H. pylori infection, with a particular focus on its virulence factors, pathophysiology, and vaccination strategies. This review discusses various virulence factors associated with H. pylori, such as cytotoxin-associated gene A (cagA), vacuolating cytotoxin gene (vacA), outer membrane proteins (OMPs), neutrophil-activated protein (NAP), urease (ure), and catalase. The development of vaccines based on these virulence characteristics is essential for controlling infection and ensuring long-lasting protection. Various vaccination strategies and formulations have been tested in animal models; however, their effectiveness and reproducibility in humans remain uncertain. Different types of vaccines, including vector-based vaccines, inactivated whole cells, genetically modified protein-based subunits, and multiepitope nucleic acid (DNA) vaccines, have been explored. While some vaccines have demonstrated promising results in murine models, only a limited number have been successfully tested in humans. This article provides a thorough evaluation of recent research on H. pylori virulence genes and vaccination methods, offering valuable insights for future strategies to address this global health challenge.
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Affiliation(s)
- Ayman Elbehiry
- Department of Public Health, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Eman Marzouk
- Department of Public Health, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Adil Abalkhail
- Department of Public Health, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Wael Sindi
- Department of Population, Public and Environmental Health, General Administration of Health Services, Ministry of Defense, Riyadh, Saudi Arabia
| | - Yasir Alzahrani
- Department of Psychiatry, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
| | - Salem Alhifani
- Department of Psychiatry, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
| | - Turki Alshehri
- Department of Dental, Alhada Armed Forces Hospital, Taif, Saudi Arabia
| | - Nuha Abdulaziz Anajirih
- Department of Medical Emergency Services, Faculty of Health Sciences, Umm Al-Qura University, Al-Qunfudah, Saudi Arabia
| | - Turki ALMutairi
- Department of Education and Training, Prince Sultan Military College of Health Sciences, Dammam, Saudi Arabia
| | - Ahmad Alsaedi
- Department of Education and Training, Prince Sultan Military College of Health Sciences, Dammam, Saudi Arabia
| | - Feras Alzaben
- Department of Food Service, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
| | - Abdullah Alqrni
- Department of Preventive Medicine, King Fahad Armed Hospital, Jeddah, Saudi Arabia
| | - Abdelmaged Draz
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Abdulaziz M. Almuzaini
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Sahar N. Aljarallah
- Department of Pharmacy Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia
| | - Abdulrahman Almujaidel
- Department of Public Health, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Akram Abu-Okail
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
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Talayev V, Svetlova M, Zaichenko I, Voronina E, Babaykina O, Neumoina N, Perfilova K. CCR6 + T helper cells and regulatory T cells in the blood and gastric mucosa during Helicobacter pylori infection. Helicobacter 2024; 29:e13097. [PMID: 38819071 DOI: 10.1111/hel.13097] [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: 01/23/2024] [Revised: 05/13/2024] [Accepted: 05/15/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) can evade the host's immune response and persist for a long time on the gastric mucosa. T helper (Th) cells appear to be involved in the control of H. pylori bacteria but promote mucosal inflammation. In contrast, regulatory T cells (Tregs) may reduce inflammation but promote H. pylori persistence. CC motif chemokine receptor 6 (CCR6) is involved in the migration of various cells into inflamed gastric mucosa. In this study, we examined CCR6+ Th cells and CCR6+ Tregs during H. pylori infection in humans. MATERIALS AND METHODS Isolation of cells from blood and mucosal biopsies, magnetic separation of В cells, CD4+ and CD4+CCR6+CD45RO+ T cells, antigen-specific activation, B cell response in vitro, flow cytometry, determination of CD4+CD25hiFoxP3+ Tregs and various groups of Th cells. RESULTS CD4+CCR6+ blood lymphocytes from healthy donors included Th cells and Tregs. These CCR6+ Th cells produced proinflammatory cytokines and also stimulated plasma cell maturation and antibody production in vitro. H. pylori gastritis and peptic ulcer disease were associated with an increase in the number of circulate CD4+CCR6+CD45RO+ cells and the percentage of Th1, Th17 and Th1/17 cells in this lymphocyte subgroup. In H. pylori-positive patients, circulating CD4+CCR6+ cells contained a higher proportion of H. pylori-specific cells compared with their CD4+CCR6- counterparts. H. pylori infection strongly increased the content of CD4+ lymphocytes in the inflamed gastric mucosa, with the majority of these CD4+ lymphocytes expressing CCR6. CD4+CCR6+ lymphocytes from H. pylori-infected stomach included Tregs and in vivo activated T cells, some of which produced interferon-γ without ex vivo stimulation. CONCLUSION H. pylori infection causes an increase in the number of mature CD4+CCR6+ lymphocytes in the blood, with a pro-inflammatory shift in their composition and enrichment of the gastric mucosa with CD4+CCR6+ lymphocytes, including CCR6+ Th1 cells and Tregs.
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Affiliation(s)
- Vladimir Talayev
- Academician I.N. Blokhina Nizhny Novgorod Scientific Research Institute of Epidemiology and Microbiology of Rospotrebnadzor, Nizhny Novgorod, Russia
| | - Maria Svetlova
- Academician I.N. Blokhina Nizhny Novgorod Scientific Research Institute of Epidemiology and Microbiology of Rospotrebnadzor, Nizhny Novgorod, Russia
| | - Irina Zaichenko
- Academician I.N. Blokhina Nizhny Novgorod Scientific Research Institute of Epidemiology and Microbiology of Rospotrebnadzor, Nizhny Novgorod, Russia
| | - Elena Voronina
- Academician I.N. Blokhina Nizhny Novgorod Scientific Research Institute of Epidemiology and Microbiology of Rospotrebnadzor, Nizhny Novgorod, Russia
| | - Olga Babaykina
- Academician I.N. Blokhina Nizhny Novgorod Scientific Research Institute of Epidemiology and Microbiology of Rospotrebnadzor, Nizhny Novgorod, Russia
| | - Natalia Neumoina
- Academician I.N. Blokhina Nizhny Novgorod Scientific Research Institute of Epidemiology and Microbiology of Rospotrebnadzor, Nizhny Novgorod, Russia
| | - Ksenia Perfilova
- Academician I.N. Blokhina Nizhny Novgorod Scientific Research Institute of Epidemiology and Microbiology of Rospotrebnadzor, Nizhny Novgorod, Russia
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Guan X, Ning J, Fu W, Wang Y, Zhang J, Ding S. Helicobacter pylori with trx1 high expression promotes gastric diseases via upregulating the IL23A/NF-κB/IL8 pathway. Helicobacter 2024; 29:e13072. [PMID: 38686467 DOI: 10.1111/hel.13072] [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: 11/01/2023] [Revised: 03/19/2024] [Accepted: 03/28/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND Helicobacter pylori infection is one of the main causes of gastric cancer. thioredoxin-1 (Trx1) and arginase (RocF) expressed by H. pylori were found to be closely related to its pathogenicity. However, whether Trx1 and RocF can be used in clinical screening of highly pathogenic H. pylori and the pathogenesis of trx1 high expressing H. pylori remain still unknown. MATERIALS AND METHODS We investigated the expression level of H. pylori trx1 and H. pylori rocF in human gastric antrum tissues using reverse transcription and quantitative real-time PCR (RT-qPCR) and clarified the clinical application value of trx1 and rocF for screening highly pathogenic H. pylori. The pathogenic mechanism of Trx1 were further explored by RNA-seq of GES-1 cells co-cultured with trx1 high or low expressing H. pylori. Differentially expressed genes and signaling pathways were validated by RT-qPCR, Enzyme-linked immunosorbent assay (ELISA), western blot, immunohistochemistry and immunofluorescence. We also assessed the adherence of trx1 high and low expressing H. pylori to GES-1 cells. RESULTS We found that H. pylori trx1 and H. pylori rocF were more significantly expressed in the gastric cancer and peptic ulcer group than that in the gastritis group and the parallel diagnosis of H. pylori trx1 and H. pylori rocF had high sensitivity. The trx1 high expressing H. pylori had stronger adhesion ability to GES-1 cells and upregulated the interleukin (IL) 23A/nuclear factor κappaB (NF-κB)/IL17A, IL6, IL8 pathway. CONCLUSIONS H. pylori trx1 and H. pylori rocF can be used in clinical screening of highly pathogenic H. pylori and predicting the outcome of H. pylori infection. The trx1 high expressing H. pylori has stronger adhesion capacity and promotes the development of gastric diseases by upregulating the activation of NF-κB signaling pathway.
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Affiliation(s)
- Xin Guan
- Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Jing Ning
- Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Weiwei Fu
- Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Ye Wang
- Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Jing Zhang
- Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Shigang Ding
- Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Department of Gastroenterology, Peking University Third Hospital, Beijing, China
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6
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Engelsberger V, Gerhard M, Mejías-Luque R. Effects of Helicobacter pylori infection on intestinal microbiota, immunity and colorectal cancer risk. Front Cell Infect Microbiol 2024; 14:1339750. [PMID: 38343887 PMCID: PMC10853882 DOI: 10.3389/fcimb.2024.1339750] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/10/2024] [Indexed: 02/15/2024] Open
Abstract
Infecting about half of the world´s population, Helicobacter pylori is one of the most prevalent bacterial infections worldwide and the strongest known risk factor for gastric cancer. Although H. pylori colonizes exclusively the gastric epithelium, the infection has also been associated with various extragastric diseases, including colorectal cancer (CRC). Epidemiological studies reported an almost two-fold increased risk for infected individuals to develop CRC, but only recently, direct causal and functional links between the chronic infection and CRC have been revealed. Besides modulating the host intestinal immune response, H. pylori is thought to increase CRC risk by inducing gut microbiota alterations. It is known that H. pylori infection not only impacts the gastric microbiota at the site of infection but also leads to changes in bacterial colonization in the distal large intestine. Considering that the gut microbiome plays a driving role in CRC, H. pylori infection emerges as a key factor responsible for promoting changes in microbiome signatures that could contribute to tumor development. Within this review, we want to focus on the interplay between H. pylori infection, changes in the intestinal microbiota, and intestinal immunity. In addition, the effects of H. pylori antibiotic eradication therapy will be discussed.
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Affiliation(s)
| | | | - Raquel Mejías-Luque
- Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Department Preclinical Medicine, Technical University of Munich, Munich, Germany
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Neuper T, Frauenlob T, Dang HH, Krenn PW, Posselt G, Regl C, Fortelny N, Schäpertöns V, Unger MS, Üblagger G, Neureiter D, Mühlbacher I, Weitzendorfer M, Singhartinger F, Emmanuel K, Huber CG, Wessler S, Aberger F, Horejs-Hoeck J. ADP-heptose attenuates Helicobacter pylori-induced dendritic cell activation. Gut Microbes 2024; 16:2402543. [PMID: 39288239 PMCID: PMC11409497 DOI: 10.1080/19490976.2024.2402543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/25/2024] [Accepted: 07/29/2024] [Indexed: 09/19/2024] Open
Abstract
Sophisticated immune evasion strategies enable Helicobacter pylori (H. pylori) to colonize the gastric mucosa of approximately half of the world's population. Persistent infection and the resulting chronic inflammation are a major cause of gastric cancer. To understand the intricate interplay between H. pylori and host immunity, spatial profiling was used to monitor immune cells in H. pylori infected gastric tissue. Dendritic cell (DC) and T cell phenotypes were further investigated in gastric organoid/immune cell co-cultures and mechanistic insights were acquired by proteomics of human DCs. Here, we show that ADP-heptose, a bacterial metabolite originally reported to act as a bona fide PAMP, reduces H. pylori-induced DC maturation and subsequent T cell responses. Mechanistically, we report that H. pylori uptake and subsequent DC activation by an ADP-heptose deficient H. pylori strain depends on TLR2. Moreover, ADP-heptose attenuates full-fledged activation of primary human DCs in the context of H. pylori infection by impairing type I IFN signaling. This study reveals that ADP-heptose mitigates host immunity during H. pylori infection.
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Affiliation(s)
- Theresa Neuper
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Tobias Frauenlob
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Hieu-Hoa Dang
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Peter W Krenn
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Gernot Posselt
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Christof Regl
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Nikolaus Fortelny
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Veronika Schäpertöns
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
| | - Michael S Unger
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
| | - Gunda Üblagger
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
| | - Daniel Neureiter
- Cancer Cluster Salzburg, Salzburg, Austria
- Institute of Pathology, Uniklinikum Salzburg, Salzburg, Austria
| | - Iris Mühlbacher
- Department of General, Visceral and Thoracic Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
| | - Michael Weitzendorfer
- Department of General, Visceral and Thoracic Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
| | - Franz Singhartinger
- Department of General, Visceral and Thoracic Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
| | - Klaus Emmanuel
- Cancer Cluster Salzburg, Salzburg, Austria
- Department of General, Visceral and Thoracic Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
| | - Christian G Huber
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Silja Wessler
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Fritz Aberger
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Jutta Horejs-Hoeck
- Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Salzburg, Austria
- Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
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Liu Q, Chen C, He Y, Mai W, Ruan S, Ning Y, Li Y. Notch Signaling Regulates the Function and Phenotype of Dendritic Cells in Helicobacter pylori Infection. Microorganisms 2023; 11:2818. [PMID: 38004829 PMCID: PMC10673485 DOI: 10.3390/microorganisms11112818] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Notch signaling manipulates the function and phenotype of dendritic cells (DCs), as well as the interaction between DCs and CD4+ T cells. However, the role of Notch signaling in Helicobacter pylori (H. pylori) infection remains elusive. Murine bone marrow-derived dendritic cells (BMDCs) were pretreated in the absence or presence of Notch signaling inhibitor DAPT prior to H. pylori stimulation and the levels of Notch components, cytokines and surface markers as well as the differentiation of CD4+ T cells in co-culture were measured using quantitative real-time PCR (qRT-PCR), Western blot, enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Compared with the control, the mRNA expression of all Notch receptors and Notch ligands Dll4 and Jagged1 was up-regulated in H. pylori-stimulated BMDCs. The blockade of Notch signaling by DAPT influenced the production of IL-1β and IL-10 in H. pylori-pulsed BMDCs, and reduced the expression of Notch1, Notch3, Notch4, Dll1, Dll3 and Jagged2. In addition, DAPT pretreatment decreased the expression of maturation markers CD80, CD83, CD86, and major histocompatibility complex class II (MHC-II) of BMDCs, and further skewed Th17/Treg balance toward Treg. Notch signaling regulates the function and phenotype of DCs, thus mediating the differentiation of CD4+ T cells during H. pylori infection.
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Affiliation(s)
| | | | | | | | | | - Yunshan Ning
- School of Laboratory Medicine and Biotechnology, Southern Medical University, No. 1023, South Shatai Road, Baiyun District, Guangzhou 510515, China (W.M.)
| | - Yan Li
- School of Laboratory Medicine and Biotechnology, Southern Medical University, No. 1023, South Shatai Road, Baiyun District, Guangzhou 510515, China (W.M.)
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9
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Innate immune activation and modulatory factors of Helicobacter pylori towards phagocytic and nonphagocytic cells. Curr Opin Immunol 2023; 82:102301. [PMID: 36933362 DOI: 10.1016/j.coi.2023.102301] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 02/17/2023] [Indexed: 03/18/2023]
Abstract
Helicobacter pylori is an intriguing obligate host-associated human pathogen with a specific host interaction biology, which has been shaped by thousands of years of host-pathogen coevolution. Molecular mechanisms of interaction of H. pylori with the local immune cells in the human system are less well defined than epithelial cell interactions, although various myeloid cells, including neutrophils and other phagocytes, are locally present or attracted to the sites of infection and interact with H. pylori. We have recently addressed the question of novel bacterial innate immune stimuli, including bacterial cell envelope metabolites, that can activate and modulate cell responses via the H. pylori Cag type IV secretion system. This review article gives an overview of what is currently known about the interaction modes and mechanisms of H. pylori with diverse human cell types, with a focus on bacterial metabolites and cells of the myeloid lineage including phagocytic and antigen-presenting cells.
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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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Cheok YY, Tan GMY, Lee CYQ, Abdullah S, Looi CY, Wong WF. Innate Immunity Crosstalk with Helicobacter pylori: Pattern Recognition Receptors and Cellular Responses. Int J Mol Sci 2022; 23:ijms23147561. [PMID: 35886908 PMCID: PMC9317022 DOI: 10.3390/ijms23147561] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/02/2022] [Accepted: 07/04/2022] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori is one of the most successful gastric pathogens that has co-existed with human for centuries. H. pylori is recognized by the host immune system through human pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), C-type lectin like receptors (CLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs), which activate downstream signaling pathways. Following bacterial recognition, the first responders of the innate immune system, including neutrophils, macrophages, and dendritic cells, eradicate the bacteria through phagocytic and inflammatory reaction. This review provides current understanding of the interaction between the innate arm of host immunity and H. pylori, by summarizing H. pylori recognition by PRRs, and the subsequent signaling pathway activation in host innate immune cells.
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Affiliation(s)
- Yi Ying Cheok
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia; (Y.Y.C.); (G.M.Y.T.); (C.Y.Q.L.)
| | - Grace Min Yi Tan
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia; (Y.Y.C.); (G.M.Y.T.); (C.Y.Q.L.)
| | - Chalystha Yie Qin Lee
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia; (Y.Y.C.); (G.M.Y.T.); (C.Y.Q.L.)
| | - Suhailah Abdullah
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia;
| | - Chung Yeng Looi
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, Subang Jaya 47500, Malaysia;
| | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia; (Y.Y.C.); (G.M.Y.T.); (C.Y.Q.L.)
- Correspondence:
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Vaillant L, Oster P, McMillan B, Orozco Fernandez E, Velin D. GM-CSF is key in the efficacy of vaccine-induced reduction of Helicobacter pylori infection. Helicobacter 2022; 27:e12875. [PMID: 35092634 PMCID: PMC9285700 DOI: 10.1111/hel.12875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 11/22/2021] [Accepted: 01/16/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) colonizes the human gastric mucosa with a high worldwide prevalence. Currently, H. pylori is eradicated by the use of antibiotics. However, elevated antibiotic resistance suggests new therapeutic strategies need to be envisioned: one approach being prophylactic vaccination. Pre-clinical and clinical data show that a urease-based vaccine is efficient in decreasing H. pylori infection through the mobilization of T helper (Th) cells, especially Th17 cells. Th17 cells produce interleukins such as IL-22 and IL-17, among others, and are key players in vaccine efficacy. Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing Th17 cells have been identified. AIM This study explores the possibility that GM-CSF plays a role in the reduction of H. pylori infection following vaccination. RESULTS We demonstrate that GM-CSF+ IL-17+ Th17 cells accumulate in the stomach mucosa of H. pylori infected mice during the vaccine-induced reduction of H. pylori infection. Secondly, we provide evidence that vaccinated GM-CSF deficient mice only modestly reduce H. pylori infection. Conversely, we observe that an increase in GM-CSF availability reduces H. pylori burden in chronically infected mice. Thirdly, we show that GM-CSF, by acting on gastric epithelial cells, promotes the production of βdefensin3, which exhibits H. pylori bactericidal activities. CONCLUSION Taken together, we demonstrate a key role of GM-CSF, most probably originating from Th17 cells, in the vaccine-induced reduction of H. pylori infection.
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Affiliation(s)
- Laurie Vaillant
- Service of Gastroenterology and HepatologyCentre Hospitalier Universitaire VaudoisUniversity of LausanneLausanneSwitzerland
| | - Paul Oster
- Service of Gastroenterology and HepatologyCentre Hospitalier Universitaire VaudoisUniversity of LausanneLausanneSwitzerland
| | - Brynn McMillan
- Service of Gastroenterology and HepatologyCentre Hospitalier Universitaire VaudoisUniversity of LausanneLausanneSwitzerland
| | - Eulalia Orozco Fernandez
- Service of Gastroenterology and HepatologyCentre Hospitalier Universitaire VaudoisUniversity of LausanneLausanneSwitzerland
| | - Dominique Velin
- Service of Gastroenterology and HepatologyCentre Hospitalier Universitaire VaudoisUniversity of LausanneLausanneSwitzerland
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Tilahun M, Gedefie A, Belayhun C, Sahle Z, Abera A. Helicobacter pylori Pathogenicity Islands and Giardia lamblia Cysteine Proteases in Role of Coinfection and Pathogenesis. Infect Drug Resist 2022; 15:21-34. [PMID: 35023934 PMCID: PMC8747529 DOI: 10.2147/idr.s346705] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/21/2021] [Indexed: 12/18/2022] Open
Abstract
Helicobacter pylori is a well-known human-specific stomach pathogen that infects more than half of the world’s population. The infection with this bacterium can cause a variety of gastrointestinal problems, including chronic gastritis, peptic ulcers, and even cancer. H. pylori is a highly infectious bacterium. H. pylori causes an increase in gastric mucosa pH or gastric mucosa intestinal metaplasia. These modifications in the stomach environment are necessary for G. lamblia colonization to occur. Giardia lamblia is a flagellate protozoan parasite that can cause giardiasis in humans and other mammals. It dwells in the duodenum and upper jejunum. Globally, over 280 million cases of human giardiasis are predicted to occur each year. Simultaneous human colonization by G. lamblia and H. pylori is a typical occurrence since the viruses’ predisposing factors are similar in both groups. Giardiasis is a parasitic infection that affects both children and adults worldwide. Infection with Giardia is more common in underdeveloped countries. Globally, more than 200 million cases of giardiasis are detected each year. In contrast, the presence of G. lamblia in the host body triggers an immunological response comparable to that of H. pylori, with lymphocytes strongly polarized towards Th1. As a result, their combined presence exacerbates host tissue damage. The major goal of this seminar is to describe the pathophysiology, immunology, and clinical aspects of G. lamblia and H. pylori coinfection using a comprehensive search of PubMed, Lancet, and Google Scholar sources. Upper gastrointestinal problems such as upper abdominal pain, abdominal bloating, nausea, vomiting, epigastric pain/burning, and belching are all caused by both organisms. Differentiation by physical examination is impossible in people infected with both bacteria. For this coinfection distinction, a laboratory diagnosis is required. G. lamblia and H. pylori, when present together, have a synergistic effect on the host and can cause serious damage. As a result, researchers should delve deeper into the mechanics underlying this potential microbial interaction.
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Affiliation(s)
- Mihret Tilahun
- Department of Medical Laboratory Sciences, College of Medicine and Health Science, Wollo University, Dessie, Ethiopia
| | - Alemu Gedefie
- Department of Medical Laboratory Sciences, College of Medicine and Health Science, Wollo University, Dessie, Ethiopia
| | - Chernet Belayhun
- Department of Medical Laboratory Science, Mehal Meda Hospital, North Showa, Ethiopia
| | - Zenawork Sahle
- Department of Medical Laboratory Science, Debre Birhan Health Science College, North Showa, Ethiopia
| | - Admasu Abera
- Department of Medical Laboratory Science, Debre Birhan Health Science College, North Showa, Ethiopia
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Hoft SG, Noto CN, DiPaolo RJ. Two Distinct Etiologies of Gastric Cancer: Infection and Autoimmunity. Front Cell Dev Biol 2021; 9:752346. [PMID: 34900999 PMCID: PMC8661534 DOI: 10.3389/fcell.2021.752346] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 11/12/2021] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is a leading cause of mortality worldwide. The risk of developing gastric adenocarcinoma, which comprises >90% of gastric cancers, is multifactorial, but most associated with Helicobacter pylori infection. Autoimmune gastritis is a chronic autoinflammatory syndrome where self-reactive immune cells are activated by gastric epithelial cell autoantigens. This cause of gastritis is more so associated with the development of neuroendocrine tumors. However, in both autoimmune and infection-induced gastritis, high risk metaplastic lesions develop within the gastric mucosa. This warrants concern for carcinogenesis in both inflammatory settings. There are many similarities and differences in disease progression between these two etiologies of chronic gastritis. Both diseases have an increased risk of gastric adenocarcinoma development, but each have their own unique comorbidities. Autoimmune gastritis is a primary cause of pernicious anemia, whereas chronic infection typically causes gastrointestinal ulceration. Both immune responses are driven by T cells, primarily CD4+ T cells of the IFN-γ producing, Th1 phenotype. Neutrophilic infiltrates help clear H. pylori infection, but neutrophils are not necessarily recruited in the autoimmune setting. There have also been hypotheses that infection with H. pylori initiates autoimmune gastritis, but the literature is far from definitive with evidence of infection-independent autoimmune gastric disease. Gastric cancer incidence is increasing among young women in the United States, a population at higher risk of developing autoimmune disease, and H. pylori infection rates are falling. Therefore, a better understanding of these two chronic inflammatory diseases is needed to identify their roles in initiating gastric cancer.
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Affiliation(s)
- Stella G Hoft
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, United States
| | - Christine N Noto
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, United States
| | - Richard J DiPaolo
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, United States
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HIV-1 Nef Induces Hck/Lyn-Dependent Expansion of Myeloid-Derived Suppressor Cells Associated with Elevated Interleukin-17/G-CSF Levels. J Virol 2021; 95:e0047121. [PMID: 34106001 PMCID: PMC8354241 DOI: 10.1128/jvi.00471-21] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection causes myelodysplasia, anemia, and accumulation of inflammatory monocytes (CD14+ CD16+) through largely unknown cellular and molecular pathways. The mouse cells thought to be equivalent to human CD14+ CD16+ cells are CD11b+ Gr1+ myeloid-derived suppressor cells (MDSC). We used HIV transgenic (Tg) mouse models to study MDSC, namely, CD4C/Nef Tg mice expressing nef in dendritic cells (DC), pDC, CD4+ T, and other mature and immature myeloid cells and CD11c/Nef Tg mice with a more restricted expression, mainly in DC and pDC. Both Tg strains showed expansion of granulocytic and CD11b+ Gr1low/int cells with MDSC characteristics. Fetal liver cell transplantation revealed that this expansion was stroma-independent and abrogated in mixed Tg/non-Tg 50% chimera. Tg bone marrow (BM) erythroid progenitors were decreased and myeloid precursors increased, suggesting an aberrant differentiation likely driving CD11b+ Gr1+ cell expansion, apparently cell autonomously in CD4C/Nef Tg mice and likely through a bystander effect in CD11c/Nef Tg mice. Hck was activated in Tg spleen, and Nef-mediated CD11b+ Gr1+ cell expansion was abrogated in Hck/Lyn-deficient Nef Tg mice, indicating a requirement of Hck/Lyn for this Nef function. IL-17 and granulocyte colony-stimulating factor (G-CSF) were elevated in Nef Tg mice. Increased G-CSF levels were normalized in Tg mice treated with anti-IL-17 antibodies. Therefore, Nef expression in myeloid precursors causes severe BM failure, apparently cell autonomously. More cell-restricted expression of Nef in DC and pDC appears sufficient to induce BM differentiation impairment, granulopoiesis, and expansion of MDSC at the expense of erythroid maturation, with IL-17→G-CSF as one likely bystander contributor. IMPORTANCE HIV-1 and SIV infection often lead to myelodysplasia, anemia, and accumulation of inflammatory monocytes (CD14+ CD16+), with the latter likely involved in neuroAIDS. We found that some transgenic (Tg) mouse models of AIDS also develop accumulation of mature and immature cells of the granulocytic lineage, decreased erythroid precursors, and expansion of MDSC (equivalent to human CD14+ CD16+ cells). We identified Nef as being responsible for these phenotypes, and its expression in mouse DC appears sufficient for their development through a bystander mechanism. Nef expression in myeloid progenitors may also favor myeloid cell expansion, likely in a cell-autonomous way. Hck/Lyn is required for the Nef-mediated accumulation of myeloid cells. Finally, we identified G-CSF under the control of IL-17 as one bystander mediator of MDSC expansion. Our findings provide a framework to determine whether the Nef>Hck/Lyn>IL-17>G-CSF pathway is involved in human AIDS and whether it represents a valid therapeutic target.
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Thein W, Po WW, Choi WS, Sohn UD. Autophagy and Digestive Disorders: Advances in Understanding and Therapeutic Approaches. Biomol Ther (Seoul) 2021; 29:353-364. [PMID: 34127572 PMCID: PMC8255139 DOI: 10.4062/biomolther.2021.086] [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: 05/01/2021] [Revised: 05/11/2021] [Accepted: 05/24/2021] [Indexed: 12/16/2022] Open
Abstract
The gastrointestinal (GI) tract is a series of hollow organs that is responsible for the digestion and absorption of ingested foods and the excretion of waste. Any changes in the GI tract can lead to GI disorders. GI disorders are highly prevalent in the population and account for substantial morbidity, mortality, and healthcare utilization. GI disorders can be functional, or organic with structural changes. Functional GI disorders include functional dyspepsia and irritable bowel syndrome. Organic GI disorders include inflammation of the GI tract due to chronic infection, drugs, trauma, and other causes. Recent studies have highlighted a new explanatory mechanism for GI disorders. It has been suggested that autophagy, an intracellular homeostatic mechanism, also plays an important role in the pathogenesis of GI disorders. Autophagy has three primary forms: macroautophagy, microautophagy, and chaperone-mediated autophagy. It may affect intestinal homeostasis, host defense against intestinal pathogens, regulation of the gut microbiota, and innate and adaptive immunity. Drugs targeting autophagy could, therefore, have therapeutic potential for treating GI disorders. In this review, we provide an overview of current understanding regarding the evidence for autophagy in GI diseases and updates on potential treatments, including drugs and complementary and alternative medicines.
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Affiliation(s)
- Wynn Thein
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Wah Wah Po
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Won Seok Choi
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Uy Dong Sohn
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
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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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Go DM, Lee SH, Lee SH, Woo SH, Kim K, Kim K, Park KS, Park JH, Ha SJ, Kim WH, Choi JH, Kim DY. Programmed Death Ligand 1-Expressing Classical Dendritic Cells MitigateHelicobacter-Induced Gastritis. Cell Mol Gastroenterol Hepatol 2021; 12:715-739. [PMID: 33894424 PMCID: PMC8267570 DOI: 10.1016/j.jcmgh.2021.04.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 04/13/2021] [Accepted: 04/13/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Helicobacter pylori has been reported to modulate local immune responses to colonize persistently in gastric mucosa. Although the induced expression of programmed cell death ligand 1 (PD-L1) has been suggested as an immune modulatory mechanism for persistent infection of H pylori, the main immune cells expressing PD-L1 and their functions in Helicobacter-induced gastritis still remain to be elucidated. METHODS The blockades of PD-L1 with antibody or PD-L1-deficient bone marrow transplantation were performed in Helicobacter-infected mice. The main immune cells expressing PD-L1 in Helicobacter-infected stomach were determined by flow cytometry and immunofluorescence staining. Helicobacter felis or H pylori-infected dendritic cell (DC)-deficient mouse models including Flt3-/-, Zbtb46-diphtheria toxin receptor, and BDCA2-diphtheria toxin receptor mice were analyzed for pathologic changes and colonization levels. Finally, the location of PD-L1-expressing DCs and the correlation with H pylori infection were analyzed in human gastric tissues using multiplexed immunohistochemistry. RESULTS Genetic or antibody-mediated blockade of PD-L1 aggravated Helicobacter-induced gastritis with mucosal metaplasia. Gastric classical DCs expressed considerably higher levels of PD-L1 than other immune cells and co-localized with T cells in gastritis lesions from Helicobacter-infected mice and human beings. H felis- or H pylori-infected Flt3-/- or classical DC-depleted mice showed aggravated gastritis with severe T-cell and neutrophil accumulation with low bacterial loads compared with that in control mice. Finally, PD-L1-expressing DCs were co-localized with T cells and showed a positive correlation with H pylori infection in human subjects. CONCLUSIONS The PD-1/PD-L1 pathway may be responsible for the immune modulatory function of gastric DCs that protects the gastric mucosa from Helicobacter-induced inflammation, but allows persistent Helicobacter colonization.
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Affiliation(s)
- Du-Min Go
- Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Seung Hyun Lee
- Department of Life Sciences, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea
| | - Su-Hyung Lee
- Division of Cancer Biology, Research Institute of National Cancer Center, Gyeonggi-do, Republic of Korea
| | - Sang-Ho Woo
- Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Kibyeong Kim
- Department of Life Sciences, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea
| | - Kyeongdae Kim
- Department of Life Sciences, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea
| | - Kyu Seong Park
- Department of Life Sciences, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea
| | - Jong-Hwan Park
- Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea
| | - Sang-Jun Ha
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Woo Ho Kim
- Department of Pathology, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Jae-Hoon Choi
- Department of Life Sciences, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea.
| | - Dae-Yong Kim
- Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
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Sarajlic M, Neuper T, Vetter J, Schaller S, Klicznik MM, Gratz IK, Wessler S, Posselt G, Horejs-Hoeck J. H. pylori modulates DC functions via T4SS/TNFα/p38-dependent SOCS3 expression. Cell Commun Signal 2020; 18:160. [PMID: 33023610 PMCID: PMC7541176 DOI: 10.1186/s12964-020-00655-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 09/06/2020] [Indexed: 12/11/2022] Open
Abstract
Background Helicobacter pylori (H. pylori) is a gram-negative bacterium that chronically infects approximately 50% of the world’s human population. While in most cases the infection remains asymptomatic, 10% of infected individuals develop gastric pathologies and 1–3% progress to gastric cancer. Although H. pylori induces severe inflammatory responses, the host’s immune system fails to clear the pathogen and H. pylori can persist in the human stomach for decades. As suppressor of cytokine signaling (SOCS) proteins are important feedback regulators limiting inflammatory responses, we hypothesized that H. pylori could modulate the host’s immune responses by inducing SOCS expression. Methods The phenotype of human monocyte-derived DCs (moDCs) infected with H. pylori was analyzed by flow cytometry and multiplex technology. SOCS expression levels were monitored by qPCR and signaling studies were conducted by means of Western blot. For functional studies, RNA interference-based silencing of SOCS1–3 and co-cultures with CD4+ T cells were performed. Results We show that H. pylori positive gastritis patients express significantly higher SOCS3, but not SOCS1 and SOCS2, levels compared to H. pylori negative patients. Moreover, infection of human moDCs with H. pylori rapidly induces SOCS3 expression, which requires the type IV secretion system (T4SS), release of TNFα, and signaling via the MAP kinase p38, but appears to be independent of TLR2, TLR4, MEK1/2 and STAT proteins. Silencing of SOCS3 expression in moDCs prior to H. pylori infection resulted in increased release of both pro- and anti-inflammatory cytokines, upregulation of PD-L1, and decreased T-cell proliferation. Conclusions This study shows that H. pylori induces SOCS3 via an autocrine loop involving the T4SS and TNFα and p38 signaling. Moreover, we demonstrate that high levels of SOCS3 in DCs dampen PD-L1 expression on DCs, which in turn drives T-cell proliferation.
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