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Moskal K, Khurana N, Siegert L, Lee YS, Clevers H, Elinav E, Puschhof J. Modeling cancer-microbiome interactions in vitro: A guide to co-culture platforms. Int J Cancer 2025; 156:2053-2067. [PMID: 39716471 PMCID: PMC11970552 DOI: 10.1002/ijc.35298] [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: 07/15/2024] [Revised: 10/10/2024] [Accepted: 10/29/2024] [Indexed: 12/25/2024]
Abstract
The biology of cancer is characterized by an intricate interplay of cells originating not only from the tumor mass, but also its surrounding environment. Different microbial species have been suggested to be enriched in tumors and the impacts of these on tumor phenotypes is subject to intensive investigation. For these efforts, model systems that accurately reflect human-microbe interactions are rapidly gaining importance. Here we present a guide for selecting a suitable in vitro co-culture platform used to model different cancer-microbiome interactions. Our discussion spans a variety of in vitro models, including 2D cultures, tumor spheroids, organoids, and organ-on-a-chip platforms, where we delineate their respective advantages, limitations, and applicability in cancer microbiome research. Particular focus is placed on methodologies that facilitate the exposure of cancer cells to microbes, such as organoid microinjections and co-culture on microfluidic devices. We highlight studies offering critical insights into possible cancer-microbe interactions and underscore the importance of in vitro models in those discoveries. We anticipate the integration of more complex microbial communities and the inclusion of immune cells into co-culture systems to more accurately simulate the tumor microenvironment. The advent of ever more sophisticated co-culture models will aid in unraveling the mechanisms of cancer-microbiome interplay and contribute to exploiting their potential in novel diagnostic and therapeutic strategies.
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Affiliation(s)
- Kamil Moskal
- Junior Research Group Epithelium Microbiome Interactions (EMIL), German Cancer Research CenterHeidelbergGermany
- Microbiome and Cancer Division, German Cancer Research CenterHeidelbergGermany
- Faculty of BiosciencesHeidelberg UniversityHeidelbergGermany
- DKFZ Hector Cancer Institute at the University Medical CenterMannheimGermany
| | - Nimisha Khurana
- Junior Research Group Epithelium Microbiome Interactions (EMIL), German Cancer Research CenterHeidelbergGermany
- Microbiome and Cancer Division, German Cancer Research CenterHeidelbergGermany
- Faculty of BiosciencesHeidelberg UniversityHeidelbergGermany
| | - Luisa Siegert
- Junior Research Group Epithelium Microbiome Interactions (EMIL), German Cancer Research CenterHeidelbergGermany
- Microbiome and Cancer Division, German Cancer Research CenterHeidelbergGermany
| | - Ye Seul Lee
- Junior Research Group Epithelium Microbiome Interactions (EMIL), German Cancer Research CenterHeidelbergGermany
- Microbiome and Cancer Division, German Cancer Research CenterHeidelbergGermany
- Faculty of BiosciencesHeidelberg UniversityHeidelbergGermany
| | - Hans Clevers
- Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC UtrechtHubrecht InstituteUtrechtThe Netherlands
- Present address:
Roche Pharmaceutical Research and Early DevelopmentBaselSwitzerland
| | - Eran Elinav
- Microbiome and Cancer Division, German Cancer Research CenterHeidelbergGermany
- Systems Immunology DepartmentWeizmann Institute of ScienceRehovotIsrael
| | - Jens Puschhof
- Junior Research Group Epithelium Microbiome Interactions (EMIL), German Cancer Research CenterHeidelbergGermany
- Microbiome and Cancer Division, German Cancer Research CenterHeidelbergGermany
- Faculty of BiosciencesHeidelberg UniversityHeidelbergGermany
- DKFZ Hector Cancer Institute at the University Medical CenterMannheimGermany
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Moraes FCAD, Sobreira LER, Kelly FA, Rodríguez Burbano RM. Impact of helicobacter pylori infection status on outcomes among patients with gastric cancer treated with immune checkpoint inhibitors: A systematic review and meta-analysis. Microb Pathog 2025; 202:107407. [PMID: 39988067 DOI: 10.1016/j.micpath.2025.107407] [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: 07/08/2024] [Revised: 02/16/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
BACKGROUND Helicobacter pylori (H. pylori), a microaerophilic gram-negative bacterium, is one of the most common chronic bacterial infections in humans, affecting about 50 % of the global population. Recently, it has been proposed that H. pylori infection might impact the efficacy of immune checkpoint inhibitors (ICIs), which are used in the treatment of various cancers, including gastric cancer (GC). However, the impact of H. pylori infection on clinical outcomes in patients with GC treated with ICIs is not yet fully elucidated. OBJECTIVES Evaluating the impact of H. pylori infection status on overall survival (OS) and progression-free survival (PFS) on GC treated with ICIs. METHODS A meticulous literature search was conducted across PubMed, EMBASE, and Web of Science databases, focusing on studies that compared the effect of H. pylori-positive status versus H. pylori-negative status on patients with GC undergoing ICI treatment. The Newcastle-Ottawa Scale was utilized for the risk of bias assessment of individual studies. For binary outcomes, we used hazard ratios (HRs) or odds ratios (OR) with 95 % confidence intervals (CI) to estimate the effect size. RESULTS In total, 3 studies were included, involving 928 patients, of which 396 had H. pylori-positive status. Analysis showed that: PFS was prolonged but not statistically significant in H. pylori-negative patients (HR: 1.11; 95 % CI:0.94-1.31; p = 0.17), OS was significantly prolonged in H. pylori-negative patients (HR: 1.25; 95 % CI: 1.05-1.50; p=0.012), and the H. pylori-negative group had a significant clinical response compared with the H. pylori-positive group (OR: 0.40; 95 % CI: 0.28-0.57; p < 0.000001). CONCLUSION In this systematic review and meta-analysis, the status of H. pylori provides a perspective to reshape ICI treatment paradigms and advocates for early eradication treatment of this bacterium.
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Nikzad-Chaleshtori M, Asgari M, Rezaeizadeh G, Aali F, Doosti A. The urease E subunit vaccine stimulate the immune response versus Helicobacter pylori in animal model. Immunol Res 2025; 73:74. [PMID: 40259189 DOI: 10.1007/s12026-025-09625-6] [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: 10/30/2024] [Accepted: 03/29/2025] [Indexed: 04/23/2025]
Abstract
There is a strong association between Helicobacter pylori (H. pylori) and the occurrence of gastritis and gastric mucosal lymphoma in the human population. Vaccination is a viable preventive measure in light of the escalating issue of antibiotic resistance. The use of DNA vaccines presents a potentially effective approach. This study used the utilization of antigenic H. pylori urease E subunit (UreE) for the development of a DNA vaccine. The UreE gene was chemically cloned into pIRES2-DsRed-Express (pDNA), and PCR and restriction enzyme digestion verified the cloning. The immunogenicity and immune-protective efficacy of the vaccination were assessed in BALB/c mice. In contrast, blood samples from BALB/c mice inoculated with pDNA-UreE showed higher levels of IgG, IFN-γ, IL- 4, and IL- 17. Furthermore, stomach damage and bacterial loads were reduced, and BALB/c mice inoculated with pDNA-UreE exhibited a significant protection rate (87.5%) against the H. pylori challenge. pDNA-UreE generated a combination of Th1-Th2-Th17 immune responses, perhaps contributing to adequate protection. Based on our findings, using this DNA immunization as a preventive measure against H. pylori infection is a viable approach.
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Affiliation(s)
| | - Mohsen Asgari
- Biotechnology Research Center, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Golnoosh Rezaeizadeh
- Department of Microbiology, Falavarjan Branch, Islamic Azad University, Isfahan, Iran
| | - Faranak Aali
- Biotechnology Research Center, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Abbas Doosti
- Biotechnology Research Center, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
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Spinelli I, Porcari S, Esposito C, Fusco W, Ponziani FR, Caruso C, Savarino EV, Gasbarrini A, Cammarota G, Maida M, Facciorusso A, Ianiro G. Meta-Analysis: Inverse Association Between Helicobacter pylori Infection and Eosinophilic Oesophagitis. Aliment Pharmacol Ther 2025; 61:1096-1109. [PMID: 39991954 PMCID: PMC11908113 DOI: 10.1111/apt.70042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 01/23/2025] [Accepted: 02/10/2025] [Indexed: 02/25/2025]
Abstract
BACKGROUND Exposure to Helicobacter pylori (H. pylori) has been associated with a decreased risk of eosinophilic oesophagitis (EoE). AIM The aim of this study is to determine the association between H. pylori infection and EoE in this updated meta-analysis. METHODS We searched MEDLINE, Scopus and ISI Web of Science, through to November 2024. We included studies reporting the status of H. pylori infection in patients with and without EoE or oesophageal eosinophilia (EE). We used a random-effects model to pool estimates. RESULTS We analysed 19 studies including 1.704.821 subjects. H. pylori infection was associated with a 46% lower risk of EoE/EE (OR: 0.54, 95% CI 0.43 to 0.67). Comparable findings were observed when subgrouping studies by location or design. There was a nonsignificant decrease in odds for EoE in paediatric patients exposed to H. pylori (OR 0.57, 95% CI 0.26 to 1.24), and in studies using serology to diagnose H. pylori (OR: 0.41, 95% CI 0.16 to 1.04). We found lower odds of EoE compared with the overall findings in studies that diagnosed H. pylori only by gastric biopsy (OR 0.43, 95% CI 0.25 to 0.74) and in those published after 2019 (OR 0.44, 95% CI 0.28 to 0.68). CONCLUSIONS Exposure to H. pylori was significantly associated with decreased odds of EoE/EE. As a stronger protective effect was found in more recent studies, the epidemiology of this association may evolve and deserve to be further monitored.
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Affiliation(s)
- Irene Spinelli
- Department of Translational Medicine and SurgeryUniversità Cattolica del Sacro CuoreRomeItaly
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
| | - Serena Porcari
- Department of Translational Medicine and SurgeryUniversità Cattolica del Sacro CuoreRomeItaly
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
- Department of Medical and Surgical Sciences, UOC GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
| | - Chiara Esposito
- Department of Translational Medicine and SurgeryUniversità Cattolica del Sacro CuoreRomeItaly
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
- Department of Medical and Surgical Sciences, UOC GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
| | - William Fusco
- Department of Translational Medicine and SurgeryUniversità Cattolica del Sacro CuoreRomeItaly
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
- Department of Medical and Surgical Sciences, UOC GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
| | - Francesca Romana Ponziani
- Department of Translational Medicine and SurgeryUniversità Cattolica del Sacro CuoreRomeItaly
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
| | - Cristiano Caruso
- Department of Translational Medicine and SurgeryUniversità Cattolica del Sacro CuoreRomeItaly
- UOSD Allergologia e Immunologia ClinicaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
| | - Edoardo Vincenzo Savarino
- Department of Surgery, Oncology and GastroenterologyUniversity of PadovaPadovaItaly
- Gastroenterology UnitAzienda Ospedale Università di PadovaPadovaItaly
| | - Antonio Gasbarrini
- Department of Translational Medicine and SurgeryUniversità Cattolica del Sacro CuoreRomeItaly
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
- Department of Medical and Surgical Sciences, UOC GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
| | - Giovanni Cammarota
- Department of Translational Medicine and SurgeryUniversità Cattolica del Sacro CuoreRomeItaly
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
- Department of Medical and Surgical Sciences, UOC GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
| | - Marcello Maida
- Department of Medicine and SurgeryUniversity of Enna ‘Kore’EnnaItaly
- Gastroenterology UnitUmberto I HospitalEnnaItaly
| | - Antonio Facciorusso
- Department of Experimental MedicineUniversità del SalentoLecceItaly
- Clinical Effectiveness Research GroupUniversity of OsloOsloNorway
| | - Gianluca Ianiro
- Department of Translational Medicine and SurgeryUniversità Cattolica del Sacro CuoreRomeItaly
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
- Department of Medical and Surgical Sciences, UOC GastroenterologiaFondazione Policlinico Universitario Agostino Gemelli IRCCSRomeItaly
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Band VI, Gribonika I, Stacy A, Bouladoux N, Mistry S, Burns A, Perez-Chaparro PJ, Chau J, Enamorado M, Nagai M, Bhushan V, Golec DP, Schwartzberg PL, Hourigan SK, Nita-Lazar A, Belkaid Y. Sulfide is a keystone metabolite for gut homeostasis and immunity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.06.641928. [PMID: 40161817 PMCID: PMC11952330 DOI: 10.1101/2025.03.06.641928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Hydrogen sulfide is a gaseous, reactive molecule specifically enriched in the gastrointestinal tract. Here, we uncover a non-redundant role for sulfide in the control of both microbial and immune homeostasis of the gut. Notably, depletion of sulfide via both pharmaceutical and dietary interventions led to a profound collapse of CD4 T cells in the ileum of the small intestine lamina propria and significant impact on microbial ecology. As a result, mice with reduced sulfide within the gut were deficient in their ability to mount T cell dependent antibody responses to oral vaccine. Mechanistically, our results support the idea that sulfide could act directly on CD4 T cells via enhanced AP-1 activation, leading to heightened proliferation and cytokine production. This study uncovers sulfides as keystone components in gut ecology and provides mechanistic insight between diet, gut sulfide production and mucosal immunity.
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Affiliation(s)
- Victor I. Band
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Inta Gribonika
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Apollo Stacy
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Nicolas Bouladoux
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Shreni Mistry
- NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Andrew Burns
- NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - P. Juliana Perez-Chaparro
- NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Joanna Chau
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Michel Enamorado
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Motoyoshi Nagai
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Vanya Bhushan
- Functional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Dominic P. Golec
- Cell Signaling and Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Pamela L. Schwartzberg
- Cell Signaling and Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Suchitra K. Hourigan
- Clinical Microbiome Unit, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Aleksandra Nita-Lazar
- Functional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
| | - Yasmine Belkaid
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD 20892, USA
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Yang C, Rodriguez y Baena A, Manso BA, Hu S, Lopez-Magaña R, Ohanyan M, Ottemann KM. Helicobacter pylori luxS mutants cause hyperinflammatory responses during chronic infection. Microbiol Spectr 2025; 13:e0107324. [PMID: 39641542 PMCID: PMC11705807 DOI: 10.1128/spectrum.01073-24] [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: 04/28/2024] [Accepted: 08/30/2024] [Indexed: 12/07/2024] Open
Abstract
Helicobacter pylori infects roughly half the world's population, causing gastritis, peptic ulcers, and gastric cancer in a subset. These pathologies occur in response to a chronic inflammatory state, but it is not fully understood how H. pylori controls this process. We characterized the inflammatory response of H. pylori mutants that cannot produce the quorum sensing molecule autoinducer 2 (AI-2) by deleting the gene for the AI-2 synthase, luxS. Our work shows that H. pylori luxS mutants colonize the stomach normally but recruit high numbers of CD4+ T cells to the stomach during chronic infection. This increase in the number of CD4+ T cells correlated with elevated expression of CXCL9, a chemokine important for T cell recruitment. Together, our results suggest that H. pylori may utilize AI-2 signaling to modulate the inflammatory response during chronic infection. IMPORTANCE Many bacteria signal to each other using quorum sensing signals. One type of signal is called autoinducer 2 (AI-2), which is produced and sensed by the LuxS enzyme found in many bacteria, including the gastric pathogen Helicobacter pylori. H. pylori establishes chronic infections that last for decades and lead to serious disease outcomes. How AI-2 signaling and LuxS contribute to chronic H. pylori infection has not been studied. In this work, we analyzed how loss of H. pylori-created AI-2, via mutation of luxS, affects H. pylori chronic infection. luxS mutants did not have significant colonization defects, similar to their reported phenotype during early infection, but they did have high stomach levels of effector and regulatory T cells and T-cell-recruiting chemokines. These results suggest that H. pylori LuxS may play more of a role in modulating the immune response versus colonization.
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Affiliation(s)
- Christina Yang
- Department of Microbiology and Environmental Toxicology, University of California Santa Cruz, Santa Cruz, California, USA
| | | | - Bryce A. Manso
- Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, USA
| | - Shuai Hu
- Department of Microbiology and Environmental Toxicology, University of California Santa Cruz, Santa Cruz, California, USA
| | - Raymondo Lopez-Magaña
- Department of Microbiology and Environmental Toxicology, University of California Santa Cruz, Santa Cruz, California, USA
| | - Mané Ohanyan
- Department of Microbiology and Environmental Toxicology, University of California Santa Cruz, Santa Cruz, California, USA
| | - Karen M. Ottemann
- Department of Microbiology and Environmental Toxicology, University of California Santa Cruz, Santa Cruz, California, USA
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Chen Y, Tang Z, Tang Z, Fu L, Liang G, Zhang Y, Tao C, Wang B. Identification of core immune-related genes CTSK, C3, and IFITM1 for diagnosing Helicobacter pylori infection-associated gastric cancer through transcriptomic analysis. Int J Biol Macromol 2025; 287:138645. [PMID: 39667460 DOI: 10.1016/j.ijbiomac.2024.138645] [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: 10/01/2024] [Revised: 11/28/2024] [Accepted: 12/09/2024] [Indexed: 12/14/2024]
Abstract
OBJECTIVES To identify diagnostic genes and mechanisms linking Helicobacter pylori (H. pylori) infection to gastric cancer. METHODS Gene expression profiles from GEO were analyzed using differential expression gene (DEG) analysis, weighted gene co-expression network analysis (WGCNA), and functional enrichment. A random forest (RF) model assessed immune-related diagnostic genes, examining their expression, diagnostic performance, prognostic value, and immune cell relationships. Expression patterns of core genes were evaluated with single-cell RNA sequencing (scRNA-seq), and a regulatory network involving miRNA, mRNA, and transcription factors was built. RESULTS We identified 75 genes and developed an RF model including 15 immune-related genes, notably CTSK, NR4A3, C3, and IFITM1. Except for NR4A3, these genes showed higher expression in datasets, confirmed by in vitro tests. Their diagnostic performance had an AUC > 0.7, enhancing to >0.85 in a multi-gene model. Survival analysis linked gene upregulation to poorer prognosis, and scRNA-seq and immune cell infiltration analysis underscored their roles in immune dysregulation and pathogenicity in H. pylori-related gastric cancer. CONCLUSIONS CTSK, C3, and IFITM1 are crucial in H. pylori-related gastric cancer, forming a robust diagnostic model and guiding future diagnostic and therapeutic research.
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Affiliation(s)
- Yuzuo Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhihui Tang
- Department of Microbiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Zhuoyun Tang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lifa Fu
- Department of Microbiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Ge Liang
- Department of Microbiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Yanrong Zhang
- Department of Microbiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Chuanmin Tao
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Baoning Wang
- Department of Microbiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China.
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8
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Bhatnagar K, Jha K, Dalal N, Patki N, Gupta G, Kumar A, Kumar A, Chaudhary S. Exploring micronutrients and microbiome synergy: pioneering new paths in cancer therapy. Front Immunol 2024; 15:1442788. [PMID: 39676876 PMCID: PMC11638209 DOI: 10.3389/fimmu.2024.1442788] [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: 06/02/2024] [Accepted: 11/18/2024] [Indexed: 12/17/2024] Open
Abstract
The human microbiome is the complex ecosystem consisting of trillions of microorganisms that play a key role in developing the immune system and nutrient metabolism. Alterations in the gut microbiome have been linked to cancer initiation, progression, metastasis, and response to treatment. Accumulating evidence suggests that levels of vitamins and minerals influence the gut environment and may have implications for cancer risk and progression. Bifidobacterium has been reported to reduce the colorectal cancer risk by binding to free iron. Additionally, zinc ions have been shown to activate the immune cells and enhance the effectiveness of immunotherapy. Higher selenium levels have been associated with a reduced risk of several cancers, including colorectal cancer. In contrast, enhanced copper uptake has been implicated in promoting cancer progression, including colon cancer. The interaction between cancer and gut bacteria, as well as dysbiosis impact has been studied in animal models. The interplay between prebiotics, probiotics, synbiotics, postbiotics and gut bacteria in cancer offers the diverse physiological benefits. We also explored the particular probiotic formulations like VSL#3, Prohep, Lactobacillus rhamnosus GG (LGG), etc., for their ability to modulate immune responses and reduce tumor burden in preclinical models. Targeting the gut microbiome through antibiotics, bacteriophage, microbiome transplantation-based therapies will offer a new perspective in cancer research. Hence, to understand this interplay, we outline the importance of micronutrients with an emphasis on the immunomodulatory function of the microbiome and highlight the microbiome's potential as a target for precision medicine in cancer treatment.
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Affiliation(s)
- Kartik Bhatnagar
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Greater Noida, Uttar Pradesh, India
| | - Kanupriya Jha
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Greater Noida, Uttar Pradesh, India
| | - Nishu Dalal
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi, India
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Ninad Patki
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Greater Noida, Uttar Pradesh, India
| | - Garima Gupta
- Biological Engineering and Sciences, Indian Institute of Technology Gandhinagar Palaj, Gandhinagar, Gujarat, India
| | - Amit Kumar
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Greater Noida, Uttar Pradesh, India
| | - Anil Kumar
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi, India
| | - Sarika Chaudhary
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Greater Noida, Uttar Pradesh, India
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9
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Azami Z, Farahmand M, Kavousi M. A new multi-epitope DNA vaccine against Helicobacter Pylori infection in a BALB/c mouse model. Heliyon 2024; 10:e39433. [PMID: 39524710 PMCID: PMC11546231 DOI: 10.1016/j.heliyon.2024.e39433] [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: 05/03/2024] [Revised: 10/03/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024] Open
Abstract
Background Helicobacter Pylori (H. Pylori) is a pathogen that may invade the human stomach. This bacterial strain is now causing widespread concern and considerable health issues worldwide. In contrast to antibiotic treatment, which may lead to drug resistance, vaccination therapy is emerging as a possible immunotherapy option for H. Pylori. DNA vaccines are a potential option to traditional vaccines among vaccine research methods. Furthermore, the multiepitope DNA vaccination may induce a broader immune response to suppress H. Pylori infection. Methods Four target antigenic proteins (outer membrane beta-barrel, outer membrane beta, HofA, and hcp beta-lactamase-like protein) were used to identify epitopes. The best B and T cell epitopes were selected to induce humoral and cellular immune responses and were connected using the HEYGAEALERAG and GGGS linkers. The peptide's physicochemical characteristics, secondary and tertiary structures, antigenicity, and allergenicity were evaluated utilizing several bioinformatics tools. The multiepitope peptide was successfully inserted into the pcDNA3.1 expression vector. The immunological responses of both the vaccinated and control groups were evaluated by measuring cytokines and antibodies. Results Based on the data, the multiepitope peptide consists of 278 amino acid residues and has an average molecular weight (MW) of 28643.61 Da. The peptide residues were mainly situated within the preferred and permitted areas of the Ramachandran plot, accounting for 92.86 % of the total. The VaxiJen server has calculated that the multiepitope peptide has an antigenicity score of 1.0067. BALB/c mice vaccinated with the DNA vaccine produced significantly higher levels of specific IgG antibodies (p < 0.05). The vaccinated mice exhibited a TH1-type cellular immune response characterized by the generation of IFN-γ and a longer length of life compared to the control animals (p < 0.05). In addition, the vaccination group exhibited a substantial increase in the expression level of IFN-γ and IL-1β genes compared to the control group (p < 0.05). Conclusions The results demonstrated that the multiepitope DNA vaccine elicited significant humoral and cellular responses, and increased survival time in BALB/c mice, indicating that selecting potential epitopes may be a viable technique for developing multiepitope-based vaccines. This can help to introduce effective vaccines.
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Affiliation(s)
- Zahra Azami
- Department of Biology, East-Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Mahnaz Farahmand
- Department of Biology, East-Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Mahsa Kavousi
- Department of Biology, East-Tehran Branch, Islamic Azad University, Tehran, Iran
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10
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Safikhani Mahmoodzadeh A, Moazamian E, Shamsdin SA, Kaydani GA. Altered Cytokine Production in Patients with Helicobacter pylori Infection. Middle East J Dig Dis 2024; 16:235-241. [PMID: 39807418 PMCID: PMC11725024 DOI: 10.34172/mejdd.2024.398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 09/02/2024] [Indexed: 01/16/2025] Open
Abstract
Background Helicobacter pylori is a gram-negative pathogen. The infection caused by this pathogen may result in gastritis and can increase the risk of gastric cancer. This study investigated the relationship between H. pylori infection as the main risk factor for gastritis and changes in serum inflammatory cytokine levels. Methods Blood samples from 85 patients with stomach pain, including 46 H. pylori-positive (Hp+) and 39 H. pylori-negative (Hp-) cases, were collected and referred to a gastroenterologist. After isolation and identification of H. pylori, the severity of gastritis was determined for each patient based on the histopathological findings. Finally, the serum levels of cytokines were measured using the multiplex kit and flow cytometry methods. Results There were significant differences in the levels of interleukin-2 (IL-2), IL-4, IL-17A, IL-17F, IL-22, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) between the Hp- and the Hp+ specimens (P≤0.05). The levels of IL-2, IL-17A, IL-17F, IL-22, TNF-α, and IFN-γ were significantly higher in patients with mild and moderate gastritis than Hp- group (P≤0.05). In addition, IL-4 significantly increased in patients with moderate gastritis compared with Hp- individuals (P=0.008). Conclusion Among the inflammatory cytokines evaluated in this study, IL-17A, IL-17F, and IL-22 may play a crucial role in developing moderate gastritis in infected patients with H. pylori.
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Affiliation(s)
- Abdollah Safikhani Mahmoodzadeh
- Department of Microbiology, College of Sciences, Agriculture and Modern Technology, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Elham Moazamian
- Department of Microbiology, College of Sciences, Agriculture and Modern Technology, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Seyedeh Azra Shamsdin
- Gasteroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Gholam Abas Kaydani
- Department of Laboratory Sciences, School of Allied Medical Sciences, Ahvaze Jundishapur University of Medical Sciences, Ahvaz, Iran
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11
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Qian J, Li Z, Wang J, Lin Y, Yu Y. 6-gingerol and its derivatives inhibit Helicobacter pylori-induced gastric mucosal inflammation and improve gastrin and somatostatin secretion. Front Microbiol 2024; 15:1451563. [PMID: 39234535 PMCID: PMC11371576 DOI: 10.3389/fmicb.2024.1451563] [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: 06/19/2024] [Accepted: 07/17/2024] [Indexed: 09/06/2024] Open
Abstract
The resistance of Helicobacter pylori (H. pylori) has increased in recent years, prompting a trend in the research and development of new drugs. In our study, three derivatives (JF-1, JF-2, and JF-3) were synthesized using 6-gingerol as the main component, while JF-4, containing both 6-gingerol and 6-shogaol as the main components, was extracted from dried ginger. The minimum inhibitory concentrations (MICs), determined using the ratio dilution method, were 80 μg/mL for JF-1, 40 μg/mL for JF-2, 30 μg/mL for JF-3, 40 μg/mL for JF-4, 60 μg/mL for 6-gingerol standard (SS), and 0.03 μg/mL for amoxicillin (AMX). After treating H. pylori-infected mice, the inflammation of the gastric mucosa was suppressed. The eradication rate of H. pylori was 16.7% of JF-3 low-dose treatment (LDT), 25.0% of JF-3 high-dose treatment (HDT), 16.7% of JF-4 LDT, 16.7% of JF-4 HDT, 30% of SS LDT, 50% of SS HDT, and 36.4% of the positive control group (PCG). The levels of gastrin, somatostatin (SST), IFN-γ, IL-4, and IL-8 were significantly recovered in the JF-3 and JF-4 administration groups, but the effect was stronger in the high-dose group. These results demonstrate that 6-gingerol and its derivatives have significant anti-Helicobacter pylori effects and are promising potential treatments for H. pylori infection.
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Affiliation(s)
- Jiali Qian
- The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, Wenzhou, China
- Department of Gastroenterology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhennan Li
- The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, Wenzhou, China
- School of Medicine, Shanghai University, Shanghai, China
| | - Jinhui Wang
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yuxian Lin
- The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, Wenzhou, China
- School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, China
| | - Yingcong Yu
- The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, Wenzhou, China
- School of Medicine, Shanghai University, Shanghai, China
- The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, China
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12
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Wang Y, Liu L. Immunological factors, important players in the development of asthma. BMC Immunol 2024; 25:50. [PMID: 39060923 PMCID: PMC11282818 DOI: 10.1186/s12865-024-00644-w] [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: 05/07/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Asthma is a heterogeneous disease, and its development is the result of a combination of factors, including genetic factors, environmental factors, immune dysfunction and other factors. Its specific mechanism has not yet been fully investigated. With the improvement of disease models, research on the pathogenesis of asthma has made great progress. Immunological disorders play an important role in asthma. Previously, we thought that asthma was mainly caused by an imbalance between Th1 and Th2 immune responses, but this theory cannot fully explain the pathogenesis of asthma. Recent studies have shown that T-cell subsets such as Th1 cells, Th2 cells, Th17 cells, Tregs and their cytokines contribute to asthma through different mechanisms. For the purpose of the present study, asthma was classified into distinct phenotypes based on airway inflammatory cells, such as eosinophilic asthma, characterized by predominant eosinophil aggregates, and neutrophilic asthma, characterized by predominant neutrophil aggregates. This paper will examine the immune mechanisms underlying different types of asthma, and will utilize data from animal models and clinical studies targeting specific immune pathways to inform more precise treatments for this condition.
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Affiliation(s)
- Yang Wang
- Department of Pediatric Respiratory, Children's Medical Center，The First Hospital of Jilin University, Changchun, 130021, China
| | - Li Liu
- Department of Pediatric Respiratory, Children's Medical Center，The First Hospital of Jilin University, Changchun, 130021, China.
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13
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Jinling X, Guoan L, Chuxi C, Qiaoyuan L, Yinzhong C, Shihao C, Huaquan L, Yunxuan H, Yunshan N, Yan L. NOTCH1 is positively correlated with IL17F in Helicobacter pylori infection and a biomarker for mucosal injury. iScience 2024; 27:110323. [PMID: 39055908 PMCID: PMC11269956 DOI: 10.1016/j.isci.2024.110323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 04/26/2024] [Accepted: 06/13/2024] [Indexed: 07/28/2024] Open
Abstract
Our study previously showed the involvement of Notch1 in Th1 differentiation in H. pylori-infected patients. However, the role of Notch1 in Th17 or Treg differentiation during H. pylori infection and the potential diagnostic value of its associated genes remain unclear. Here, we found that NOTCH1 was positively correlated with Th17-related genes RORγt (r = 0.616, p < 0.001) and IL17F (r = 0.523, p < 0.01), but not with Treg-related genes FOXP3 and IL10. The mRNA levels of aforementioned genes were upregulated at different stages of mucosal injury except for upper gastrointestinal ulcers. A combiROC analysis of NOTCH1 and IL17F discriminated H. pylori-infected gastritis from healthy controls with high accuracy (AUC of 0.952, sensitivity of 0.929, and specificity of 0.893). This study is the first to show that Notch1 is correlated with Th17-associated gene expression during H. pylori infection. Additionally, NOTCH1 and IL17F are potential diagnostic markers.
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Affiliation(s)
- Xie Jinling
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
- Xinhui District People’s Hospital, Affiliated with the Southern Medical University, Jiangmen 529100, China
| | - Liu Guoan
- Xinhui District People’s Hospital, Affiliated with the Southern Medical University, Jiangmen 529100, China
| | - Chen Chuxi
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Liu Qiaoyuan
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Chen Yinzhong
- Xinhui District People’s Hospital, Affiliated with the Southern Medical University, Jiangmen 529100, China
| | - Chen Shihao
- Xinhui District People’s Hospital, Affiliated with the Southern Medical University, Jiangmen 529100, China
| | - Long Huaquan
- Xinhui District People’s Hospital, Affiliated with the Southern Medical University, Jiangmen 529100, China
| | - He Yunxuan
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Ning Yunshan
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Li Yan
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
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14
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Zhang L, Yu F, Zhang Y, Li P. Implications of lncRNAs in Helicobacter pylori-associated gastrointestinal cancers: underlying mechanisms and future perspectives. Front Cell Infect Microbiol 2024; 14:1392129. [PMID: 39035354 PMCID: PMC11257847 DOI: 10.3389/fcimb.2024.1392129] [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: 02/27/2024] [Accepted: 06/19/2024] [Indexed: 07/23/2024] Open
Abstract
Helicobacter pylori (H. pylori) is a harmful bacterium that is difficult to conveniently diagnose and effectively eradicate. Chronic H. pylori infection increases the risk of gastrointestinal diseases, even cancers. Despite the known findings, more underlying mechanisms are to be deeply explored to facilitate the development of novel prevention and treatment strategies of H. pylori infection. Long noncoding RNAs (lncRNAs) are RNAs with more than 200 nucleotides. They may be implicated in cell proliferation, inflammation and many other signaling pathways of gastrointestinal cancer progression. The dynamic expression of lncRNAs indicates their potential to be diagnostic or prognostic biomarkers. In this paper, we comprehensively summarize the processes of H. pylori infection and the treatment methods, review the known findings of lncRNA classification and functional mechanisms, elucidate the roles of lncRNAs in H. pylori-related gastrointestinal cancer, and discuss the clinical perspectives of lncRNAs.
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Affiliation(s)
- Lei Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | | | | | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
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15
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Zhang J, Wang P, Wang J, Wei X, Wang M. Unveiling intratumoral microbiota: An emerging force for colorectal cancer diagnosis and therapy. Pharmacol Res 2024; 203:107185. [PMID: 38615875 DOI: 10.1016/j.phrs.2024.107185] [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: 01/19/2024] [Revised: 04/01/2024] [Accepted: 04/11/2024] [Indexed: 04/16/2024]
Abstract
Microbes, including bacteria, viruses, fungi, and other eukaryotic organisms, are commonly present in multiple organs of the human body and contribute significantly to both physiological and pathological processes. Nowadays, the development of sequencing technology has revealed the presence and composition of the intratumoral microbiota, which includes Fusobacterium, Bifidobacteria, and Bacteroides, and has shed light on the significant involvement in the progression of colorectal cancer (CRC). Here, we summarized the current understanding of the intratumoral microbiota in CRC and outline the potential translational and clinical applications in the diagnosis, prevention, and treatment of CRC. We focused on reviewing the development of microbial therapies targeting the intratumoral microbiota to improve the efficacy and safety of chemotherapy and immunotherapy for CRC and to identify biomarkers for the diagnosis and prognosis of CRC. Finally, we emphasized the obstacles and potential solutions to translating the knowledge of the intratumoral microbiota into clinical practice.
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Affiliation(s)
- Jinjing Zhang
- Affiliated Cixi Hospital, Wenzhou Medical University, Zhejiang, China
| | - Penghui Wang
- Affiliated Cixi Hospital, Wenzhou Medical University, Zhejiang, China
| | - Jiafeng Wang
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Zhejiang, China
| | - Xiaojie Wei
- Affiliated Cixi Hospital, Wenzhou Medical University, Zhejiang, China.
| | - Mengchuan Wang
- Affiliated Cixi Hospital, Wenzhou Medical University, Zhejiang, China.
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16
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Ke Y, Tan C, Zhen J, Dong W. Global status and trends of gastric cancer and gastric microbiota research: a bibliometric analysis. Front Microbiol 2024; 15:1341012. [PMID: 38655079 PMCID: PMC11037409 DOI: 10.3389/fmicb.2024.1341012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 03/12/2024] [Indexed: 04/26/2024] Open
Abstract
Background Numerous studies have cast light on the relationship between the gastric microbiota and gastric carcinogenesis. In this study, we conducted a bibliometric analysis of the relevant literature in the field of gastric cancer and the gastric microbiota and clarified its research status, hotspots, and development trends. Materials and methods Publications were retrieved from the Web of Science Core Collection on 18 July 2023. CiteSpace 6.2.R4, VOSviewer 1.6.19.0, and Biblioshiny were used for the co-occurrence and cooperation analyses of countries, institutions, authors, references, and keywords. A keyword cluster analysis and an emergence analysis were performed, and relevant knowledge maps were drawn. Results The number of published papers in this field totaled 215 and showed an increasing trend. The analysis of funding suggested that the input in this field is increasing steadily. China had the highest number of publications, while the United States had the highest betweenness centrality. Baylor College of Medicine published the most articles cumulatively. Both Ferreira RM and Cooker OO had the highest citation frequency. The journal Helicobacter showed the most interest in this field, while Gut provided a substantial research foundation. A total of 280 keywords were obtained using CiteSpace, which were primarily focused on the eradication and pathogenic mechanisms of Helicobacter pylori, as well as the application of the gastric microbiota in the evaluation and treatment of gastric cancer. The burst analysis suggested that in the future, research may focus on the application of gastric microorganisms, particularly Fusobacterium nucleatum, in the diagnosis and treatment of gastric cancer, along with their pathogenic mechanisms. Conclusion Current studies have been tracking the eradication of Helicobacter pylori and its pathogenic mechanisms, as well as changes in the gastric microbiota during gastric carcinogenesis. Future research may focus on the clinical application and pathogenesis of stomach microorganisms through bacteria such as Fusobacterium nucleatum.
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Affiliation(s)
- Yujia Ke
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Cheng Tan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Junhai Zhen
- Department of General Practice, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Ghasemifar S, Chabak O, Piri-Gharaghie T, Doosti A. WITHDRAWN: PIRES2-EGFP/CTB-UreI vaccination activated a mixed Th1/Th2/Th17 immune system defense towards Helicobacter pylori infection in the BALB/c mice model. Vaccine 2024:125733. [PMID: 38453620 DOI: 10.1016/j.vaccine.2024.02.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 02/01/2024] [Accepted: 02/17/2024] [Indexed: 03/09/2024]
Abstract
This article has been withdrawn at the request of the Editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal. The data presented in the manuscript was deemed severely flawed after appearing online as an Article in Press. The scientific community raised concerns about the methodology (including but not limited to major technical issues) used in the study and the subsequent conclusions drawn from the presented experiments. After careful investigation, the Vaccine editorial office concluded that the data in the publication was indeed severely flawed and that the concerns raised by the scientific community were valid. Therefore, the journal editors decided to withdraw the article and sincerely apologize for any inconvenience caused.
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Affiliation(s)
- Sana Ghasemifar
- Biotechnology Research Center, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Omid Chabak
- Biotechnology Research Center, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Tohid Piri-Gharaghie
- Biotechnology Research Center, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran; Department of Biotechnology, Faculty of Basic Sciences, East-Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Abbas Doosti
- Biotechnology Research Center, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
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18
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Zhang F, Ni L, Zhang Z, Luo X, Wang X, Zhou W, Chen J, Liu J, Qu Y, Liu K, Guo L. Recombinant L. lactis vaccine LL-plSAM-WAE targeting four virulence factors provides mucosal immunity against H. pylori infection. Microb Cell Fact 2024; 23:61. [PMID: 38402145 PMCID: PMC10893618 DOI: 10.1186/s12934-024-02321-4] [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: 09/12/2023] [Accepted: 01/29/2024] [Indexed: 02/26/2024] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) causes chronic gastric disease. An efficient oral vaccine would be mucosa-targeted and offer defense against colonization of invasive infection in the digestive system. Proteolytic enzymes and acidic environment in the gastrointestinal tract (GT) can, however, reduce the effectiveness of oral vaccinations. For the creation of an edible vaccine, L. lactis has been proposed as a means of delivering vaccine antigens. RESULTS We developed a plSAM (pNZ8148-SAM) that expresses a multiepitope vaccine antigen SAM-WAE containing Urease, HpaA, HSP60, and NAP extracellularly (named LL-plSAM-WAE) to increase the efficacy of oral vaccinations. We then investigated the immunogenicity of LL-plSAM-WAE in Balb/c mice. Mice that received LL-plSAM-WAE or SAM-WAE with adjuvant showed increased levels of antibodies against H. pylori, including IgG and sIgA, and resulted in significant reductions in H. pylori colonization. Furthermore, we show that SAM-WAE and LL-plSAM-WAE improved the capacity to target the vaccine to M cells. CONCLUSIONS These findings suggest that recombinant L. lactis could be a promising oral mucosa vaccination for preventing H. pylori infection.
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Affiliation(s)
- Furui Zhang
- College of First Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China
- College of Laboratory Medicine , Ningxia Medical University, Yinchuan, 750004, China
| | - Linhan Ni
- College of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China
| | - Zhen Zhang
- Department of Geriatrics and Special Needs Medicine, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Xuegang Luo
- Key Laboratory of Industrial Fermentation Microbiology of the Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Xuequan Wang
- Key Laboratory of Radiation Oncology of Taizhou, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, 317000, China
| | - Wenmiao Zhou
- College of First Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China
| | - Jiale Chen
- College of First Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China
| | - Jing Liu
- College of Laboratory Medicine , Ningxia Medical University, Yinchuan, 750004, China
| | - Yuliang Qu
- College of Laboratory Medicine , Ningxia Medical University, Yinchuan, 750004, China.
| | - Kunmei Liu
- College of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
- Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China.
| | - Le Guo
- College of First Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China.
- College of Laboratory Medicine , Ningxia Medical University, Yinchuan, 750004, China.
- Ningxia Key Laboratory of Cerebrocranial Diseases, 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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Wu C, Jiang ML, Pang T, Zhang CJ. T Cell Subsets and Immune Homeostasis. Methods Mol Biol 2024; 2782:39-63. [PMID: 38622391 DOI: 10.1007/978-1-0716-3754-8_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2024]
Abstract
T cells are a heterogeneous group of cells that can be classified into different subtypes according to different classification methods. The body's immune system has a highly complex and effective regulatory network that allows for the relative stability of immune system function. Maintaining proper T cell homeostasis is essential for promoting protective immunity and limiting autoimmunity and tumor formation. Among the T cell family members, more and more T cell subsets have gradually been characterized. In this chapter, we summarize the functions of some key T cell subsets and their impact on immune homeostasis.
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Affiliation(s)
- Chuyu Wu
- Department of Neurology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China
| | - Mei-Ling Jiang
- Department of Neurology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Tao Pang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China
| | - Cun-Jin Zhang
- Department of Neurology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
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20
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Schorr L, Mathies M, Elinav E, Puschhof J. Intracellular bacteria in cancer-prospects and debates. NPJ Biofilms Microbiomes 2023; 9:76. [PMID: 37813921 PMCID: PMC10562400 DOI: 10.1038/s41522-023-00446-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 09/26/2023] [Indexed: 10/11/2023] Open
Abstract
Recent evidence suggests that some human cancers may harbor low-biomass microbial ecosystems, spanning bacteria, viruses, and fungi. Bacteria, the most-studied kingdom in this context, are suggested by these studies to localize within cancer cells, immune cells and other tumor microenvironment cell types, where they are postulated to impact multiple cancer-related functions. Herein, we provide an overview of intratumoral bacteria, while focusing on intracellular bacteria, their suggested molecular activities, communication networks, host invasion and evasion strategies, and long-term colonization capacity. We highlight how the integration of sequencing-based and spatial techniques may enable the recognition of bacterial tumor niches. We discuss pitfalls, debates and challenges in decisively proving the existence and function of intratumoral microbes, while reaching a mechanistic elucidation of their impacts on tumor behavior and treatment responses. Together, a causative understanding of possible roles played by intracellular bacteria in cancer may enable their future utilization in diagnosis, patient stratification, and treatment.
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Affiliation(s)
- Lena Schorr
- Microbiome and Cancer Division, German Cancer Research Center, Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Marius Mathies
- Microbiome and Cancer Division, German Cancer Research Center, Heidelberg, Germany
| | - Eran Elinav
- Microbiome and Cancer Division, German Cancer Research Center, Heidelberg, Germany.
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, 7610001, Israel.
| | - Jens Puschhof
- Microbiome and Cancer Division, German Cancer Research Center, Heidelberg, Germany.
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Magahis PT, Maron SB, Cowzer D, King S, Schattner M, Janjigian Y, Faleck D, Laszkowska M. Impact of Helicobacter pylori infection status on outcomes among patients with advanced gastric cancer treated with immune checkpoint inhibitors. J Immunother Cancer 2023; 11:e007699. [PMID: 37899129 PMCID: PMC10619027 DOI: 10.1136/jitc-2023-007699] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/22/2023] [Indexed: 10/31/2023] Open
Abstract
BACKGROUND Gut microbiota composition can influence cancer immunotherapy response. Recent evidence suggests Helicobacter pylori infection may reduce immune checkpoint inhibitor (ICI) efficacy in lung cancer and melanoma, but thorough characterization of this association in patients with gastric cancer is lacking. We aimed to determine the impact of H. pylori on survival in this population. METHODS This single-center, retrospective study included all ICI-treated individuals with metastatic gastric cancer and documented H. pylori status at Memorial Sloan Kettering between July 2013 and October 2021. H. pylori-positive status was defined as history of infection obtained via breath test, stool antigen test, histopathology, and/or chart documentation. Negative status was defined as explicitly negative testing, histopathology, and/or chart documentation. Primary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS Of 215 included patients, 49 had documented history of H. pylori infection. Compared with H. pylori-negative patients, positive individuals tended to be younger, non-white, and Hispanic with non-cardia and intestinal-type gastric cancer. H. pylori-positive patients had significantly shorter median PFS (3.2 vs 6.8 months, HR 1.96, p<0.01) and OS (9.8 vs 17.9 months, HR 1.54, p=0.02). Multivariable analysis confirmed H. pylori infection as an independent predictor of PFS (HR 3.04, p<0.01) and OS (HR 2.24, p=0.01). CONCLUSIONS In this largest study of its kind, H. pylori infection was associated with inferior survival in ICI-treated patients with gastric cancer. This suggests H. pylori status may be a prognostic marker of immune responsiveness. Future studies are needed to elucidate immunoregulatory mechanisms and whether treatment of active infections would improve immunotherapy outcomes.
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Affiliation(s)
| | - Steven B Maron
- Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Darren Cowzer
- Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Stephanie King
- Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Mark Schattner
- Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Yelena Janjigian
- Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - David Faleck
- Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Monika Laszkowska
- Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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22
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Bahuguna A, Dubey SK. Relevance of tumor microbiome in cancer incidence, prognosis, and its clinical implications in therapeutics. Biochim Biophys Acta Rev Cancer 2023; 1878:188956. [PMID: 37473857 DOI: 10.1016/j.bbcan.2023.188956] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/07/2023] [Accepted: 07/13/2023] [Indexed: 07/22/2023]
Abstract
The microbiota is garnering progressively greater consideration as an essential facet of the tumor microenvironment that regulates tumor proliferation and affects cancer prognosis. Microbial populations that inhabit different body locations are involved in the carcinogenesis and tumor progression of their corresponding malignancies. It has been learned that the microbial populations primarily thriving within tumors are tumor-type specific. Mechanistic studies have revealed that the tumor-associated microbiota contributes to playing a pivotal role in the establishment of the tumor microenvironment, regulation of local immunity, modulation of tumor cell biology, and directly influences the therapeutic efficacy of drug treatment for tumors. This review article incorporates the pertinent studies on recent advancements in tumor microbiome studies, the interplay between the intratumor microbiota and cancer, and, discusses their role and mechanism of action in the emergence and treatment of cancer, and their relationship to clinical characteristics.
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Affiliation(s)
- Ananya Bahuguna
- Department of Biochemistry, College of Basic Sciences and Humanities, Govind Ballabh Pant University of Agriculture and Technology, Pantnagar 263145, Uttarakhand, India
| | - Shiv Kumar Dubey
- Department of Biochemistry, College of Basic Sciences and Humanities, Govind Ballabh Pant University of Agriculture and Technology, Pantnagar 263145, Uttarakhand, India.
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23
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El Filaly H, Desterke C, Outlioua A, Badre W, Rabhi M, Karkouri M, Riyad M, Khalil A, Arnoult D, Akarid K. CXCL-8 as a signature of severe Helicobacter pylori infection and a stimulator of stomach region-dependent immune response. Clin Immunol 2023; 252:109648. [PMID: 37209806 DOI: 10.1016/j.clim.2023.109648] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 05/10/2023] [Accepted: 05/12/2023] [Indexed: 05/22/2023]
Abstract
Helicobacter pylori infection is involved in development of diverse gastro-pathologies. Our aim is to investigate potential signature of cytokines-chemokine levels (IL-17A, IL-1β, and CXCL-8) in H. pylori-infected patients and their impact on immune response in both corpus and antrum. Multivariate level analysis with machine learning model were carried out using cytokines/chemokine levels of infected Moroccan patients. In addition, Geo dataset was used to run enrichment analysis following CXCL-8 upregulation. Our analysis showed that combination of cytokines-chemokine levels allowed prediction of positive H. pylori density score with <5% of miss-classification error, with fundus CXCL-8 being the most important variable for this discrimination. Furthermore, CXCL-8 dependent expression profile was mainly associated to IL6/JAK/STAT3 signaling in the antrum, interferons alpha and gamma responses in the corpus and commonly induced transcriptional /proliferative activities. To conclude, CXCL-8 level might be a signature of Moroccan H. pylori-infected patients and an inducer of regional-dependent immune response at the gastric level. Larger trials must be carried out to validate the relevance of these results for diverse populations.
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Affiliation(s)
- Hajar El Filaly
- Biochemistry, Biotechnology and Immunophysiopathology Research Team, Health and Environment Laboratory, Ain Chock Faculty of Sciences, Hassan II University of Casablanca, Casablanca, Morocco
| | - Christophe Desterke
- INSERM UMRS-1311, Faculty of Medicine, University of Paris-Saclay, Villejuif, France; Biochemistry, Biotechnology and Immunophysiopathology Research Team, Health and Environment Laboratory, Ain Chock Faculty of Sciences, Hassan II University of Casablanca, Casablanca, Morocco
| | - Ahmed Outlioua
- Biochemistry, Biotechnology and Immunophysiopathology Research Team, Health and Environment Laboratory, Ain Chock Faculty of Sciences, Hassan II University of Casablanca, Casablanca, Morocco
| | - Wafaa Badre
- Gastroenterology Department, CHU IbnRochd, Casablanca, Morocco
| | - Moncef Rabhi
- Diagnostic Center, Hôpital Militaire d'Instruction Mohammed V, Mohammed V University, Rabat, Morocco
| | - Mehdi Karkouri
- Laboratory of Pathological Anatomy, CHU Ibn Rochd/Faculty of Medicine and Pharmacy, UH2C, Casablanca, Morocco
| | - Myriam Riyad
- Research Team on Immunopathology of Infectious and Systemic Diseases, Laboratory of Cellular and Molecular Pathology, Faculty of Medicine and Pharmacy, UH2C, Casablanca, Morocco
| | - Abdelouahed Khalil
- Research Center on Aging, Faculty of Medicine and Health Sciences, Department of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada
| | - Damien Arnoult
- INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France; Université Paris-Saclay, Paris, France
| | - Khadija Akarid
- Biochemistry, Biotechnology and Immunophysiopathology Research Team, Health and Environment Laboratory, Ain Chock Faculty of Sciences, Hassan II University of Casablanca, Casablanca, Morocco.
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24
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Yang H, Mou Y, Hu B. Discussion on the common controversies of Helicobacter pylori infection. Helicobacter 2023; 28:e12938. [PMID: 36436202 DOI: 10.1111/hel.12938] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 11/02/2022] [Accepted: 11/03/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Helicobacter pylori ( H. pylori ) can persistently colonize on the gastric mucosa after infection and cause gastritis, atrophy, metaplasia, and even gastric cancer (GC). METHODS Therefore, the detection and eradication of H. pylori are the prerequisite. RESULTS Clinically, there are some controversial issues, such as why H. pylori infection is persistent, why it translocases along with the lesser curvature of the stomach, why there is oxyntic antralization, what the immunological characteristic of gastric chronic inflammation caused by H. pylori is, whether H. pylori infection is associated with extra-gastric diseases, whether chronic atrophic gastritis (CAG) is reversible, and what the potential problems are after H. pylori eradication. What are the possible answers? CONCLUSION In the review, we will discuss these issues from the attachment to eradication in detail.
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Affiliation(s)
- Hang Yang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Mou
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Bing Hu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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25
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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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26
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Nelson SA, Richards KA, Glover MA, Chaves FA, Crank MC, Graham BS, Kanekiyo M, Sant AJ. CD4 T cell epitope abundance in ferritin core potentiates responses to hemagglutinin nanoparticle vaccines. NPJ Vaccines 2022; 7:124. [PMID: 36289232 PMCID: PMC9605951 DOI: 10.1038/s41541-022-00547-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 10/06/2022] [Indexed: 11/20/2022] Open
Abstract
Nanoparticle vaccines based on H. pylori ferritin are increasingly used as a vaccine platform for many pathogens, including RSV, influenza, and SARS-CoV-2. They have been found to elicit enhanced, long-lived B cell responses. The basis for improved efficacy of ferritin nanoparticle vaccines remains unresolved, including whether recruitment of CD4 T cells specific for the ferritin component of these vaccines contributes to cognate help in the B cell response. Using influenza HA-ferritin nanoparticles as a prototype, we have performed an unbiased assessment of the CD4 T cell epitope composition of the ferritin particles relative to that contributed by influenza HA using mouse models that express distinct constellations of MHC class II molecules. The role that these CD4 T cells play in the B cell responses was assessed by quantifying follicular helper cells (TFH), germinal center (GC) B cells, and antibody secreting cells. When mice were immunized with equimolar quantities of soluble HA-trimers and HA-Fe nanoparticles, HA-nanoparticle immunized mice had an increased overall abundance of TFH that were found to be largely ferritin-specific. HA-nanoparticle immunized mice had an increased abundance of HA-specific isotype-switched GC B cells and HA-specific antibody secreting cells (ASCs) relative to mice immunized with soluble HA-trimers. Further, there was a strong, positive correlation between CD4 TFH abundance and GC B cell abundance. Thus, availability of helper CD4 T cell epitopes may be a key additional mechanism that underlies the enhanced immunogenicity of ferritin-based HA-Fe-nanoparticle vaccines.
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Affiliation(s)
- Sean A Nelson
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
| | - Katherine A Richards
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
| | - Maryah A Glover
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
| | - Francisco A Chaves
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
| | - Michelle C Crank
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Institute for Asthma & Allergy, Chevy Chase, MD, USA
| | - Barney S Graham
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Masaru Kanekiyo
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Andrea J Sant
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.
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27
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Jiang ZF, Wu W, Hu HB, Li ZY, Zhong M, Zhang L. P2X7 receptor as the regulator of T-cell function in intestinal barrier disruption. World J Gastroenterol 2022; 28:5265-5279. [PMID: 36185635 PMCID: PMC9521516 DOI: 10.3748/wjg.v28.i36.5265] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 06/20/2022] [Accepted: 09/01/2022] [Indexed: 02/06/2023] Open
Abstract
The intestinal mucosa is a highly compartmentalized structure that forms a direct barrier between the host intestine and the environment, and its dysfunction could result in a serious disease. As T cells, which are important components of the mucosal immune system, interact with gut microbiota and maintain intestinal homeostasis, they may be involved in the process of intestinal barrier dysfunction. P2X7 receptor (P2X7R), a member of the P2X receptors family, mediates the effects of extracellular adenosine triphosphate and is expressed by most innate or adaptive immune cells, including T cells. Current evidence has demonstrated that P2X7R is involved in inflammation and mediates the survival and differentiation of T lymphocytes, indicating its potential role in the regulation of T cell function. In this review, we summarize the available research about the regulatory role and mechanism of P2X7R on the intestinal mucosa-derived T cells in the setting of intestinal barrier dysfunction.
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Affiliation(s)
- Zhi-Feng Jiang
- Center of Emergency & Intensive Care Unit, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Wei Wu
- Department of Critical Care Medicine, Zhongshan Hospital of Fudan University, Shanghai 200032, China
| | - Han-Bing Hu
- Center of Emergency & Intensive Care Unit, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Zheng-Yang Li
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Ming Zhong
- Department of Critical Care Medicine, Zhongshan Hospital of Fudan University, Shanghai 200032, China
| | - Lin Zhang
- Center of Emergency & Intensive Care Unit, Jinshan Hospital of Fudan University, Shanghai 201508, China
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28
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Atrisco-Morales J, Ramírez M, Castañón-Sánchez CA, Román-Román A, Román-Fernández IV, Martínez-Carrillo DN, García-Arellano S, Muñoz-Valle JF, Rodríguez-Ruiz HA, Fernández-Tilapa G. In Peripheral Blood Mononuclear Cells Helicobacter pylori Induces the Secretion of Soluble and Exosomal Cytokines Related to Carcinogenesis. Int J Mol Sci 2022; 23:ijms23158801. [PMID: 35955936 PMCID: PMC9368997 DOI: 10.3390/ijms23158801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Helicobacter pylori promotes the secretion of cytokines that regulate inflammation and carcinogenesis. Immune cells secrete cytokines into the extracellular medium or packaged in exosomes. The objective of this study was to analyze the profile of soluble and exosomal cytokines that were secreted by human peripheral blood mononuclear cells (PBMCs) that were infected with H. pylori and to build a network of interaction between cytokines and cellular proteins. PBMCs were obtained by density gradient centrifugation and infected with H. pylori for 24 h. The infection was verified by immunofluorescence and Western blot for CagA. The exosomes were obtained from culture supernatant by ultracentrifugation and characterized by transmission electron microscopy, particle size analysis, and Western blot for CD9 and CD81. Cytokines were quantified using a multiplex immunoassay in the culture supernatant, intact exosomes, and lysed exosomes. H. pylori adheres to lymphocytes and translocates CagA. In PBMCs, H. pylori induces an increase in the soluble and exosomal IL-1β, IL-6, TNF-α, IL-10, IL-17A, IL-21, and IL-22. The protein-protein interaction (PPI) network shows that soluble and exosomal cytokines interact with proteins that participate in signaling pathways such as NF-κB, MAPK, PI3K-Akt, Jak-STAT, FoxO, and mTOR, that are related to carcinogenesis; moreover, TNF-α had the highest number of interactions. Cytokine-loaded exosomes represent another means of intercellular communication that is activated by H. pylori to stimulate inflammation, carcinogenesis, or cancer progression. Cytokine-loaded exosomes are likely to be associated with extragastrointestinal diseases of inflammatory origin.
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Affiliation(s)
- Josefina Atrisco-Morales
- Laboratorio de Investigación Clínica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39087, Guerrero, Mexico
- Laboratorio de Investigación en Biomoléculas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39087, Guerrero, Mexico
| | - Mónica Ramírez
- CONACYT-Universidad Autónoma de Guerrero, Chilpancingo 39087, Guerrero, Mexico
| | - Carlos Alberto Castañón-Sánchez
- Laboratorio de Investigación Biomédica, Hospital Regional de Alta Especialidad de Oaxaca, San Bartolo Coyotepec 71256, Oaxaca, Mexico
| | - Adolfo Román-Román
- Laboratorio de Investigación en Bacteriología, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39087, Guerrero, Mexico
| | - Ilce Valeria Román-Fernández
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Dinorah Nashely Martínez-Carrillo
- Laboratorio de Investigación Clínica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39087, Guerrero, Mexico
- Laboratorio de Investigación en Biomoléculas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39087, Guerrero, Mexico
| | - Samuel García-Arellano
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Francisco Muñoz-Valle
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Hugo Alberto Rodríguez-Ruiz
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39087, Guerrero, Mexico
| | - Gloria Fernández-Tilapa
- Laboratorio de Investigación Clínica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39087, Guerrero, Mexico
- Laboratorio de Investigación en Biomoléculas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39087, Guerrero, Mexico
- Correspondence:
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Abstract
Like most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune microenvironment driven by the gram-negative bacterial species Helicobacter pylori. The infection-driven nature of most GACs has renewed awareness of the immune microenvironment and its effect on tumour development and progression. About 75-90% of GACs are associated with prior H. pylori infection and 5-10% with Epstein-Barr virus infection. Although 50% of the world's population is infected with H. pylori, only 1-3% will progress to GAC, with progression the result of a combination of the H. pylori strain, host susceptibility and composition of the chronic inflammatory response. Other environmental risk factors include exposure to a high-salt diet and nitrates. Genetically, chromosome instability occurs in ~50% of GACs and 21% of GACs are microsatellite instability-high tumours. Here, we review the timeline and pathogenesis of the events triggered by H. pylori that can create an immunosuppressive microenvironment by modulating the host's innate and adaptive immune responses, and subsequently favour GAC development.
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30
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Kountouras J, Kazakos E, Polyzos SA, Chatzopoulos D, Tzitiridou-Chatzopoulou M, Doulberis M, Papaefthymiou A, Vardaka E. GM-CSF as a potential candidate of a vaccine-induced reduction of Helicobacter pylori infection. Helicobacter 2022; 27:e12884. [PMID: 35257445 DOI: 10.1111/hel.12884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 02/19/2022] [Accepted: 02/19/2022] [Indexed: 12/09/2022]
Affiliation(s)
- Jannis Kountouras
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Macedonia, Greece
| | - Evangelos Kazakos
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Macedonia, Greece.,School of Healthcare Sciences, Midwifery Department, University of West Macedonia, Koila, Kozani, Macedonia, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Dimitrios Chatzopoulos
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Macedonia, Greece
| | - Maria Tzitiridou-Chatzopoulou
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Macedonia, Greece.,School of Healthcare Sciences, Midwifery Department, University of West Macedonia, Koila, Kozani, Macedonia, Greece
| | - Michael Doulberis
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Macedonia, Greece.,First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece.,Division of Gastroenterology and Hepatology, Medical University Department, Kantonsspital Aarau, Aarau, Switzerland
| | - Apostolis Papaefthymiou
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Macedonia, Greece.,First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece.,Department of Gastroenterology, University Hospital of Larisa, Larisa, Thessaly, Greece
| | - Elisabeth Vardaka
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Macedonia, Greece.,Department of Nutritional Sciences and Dietetics, School of Health Sciences, International Hellenic University, Thessaloniki, Macedonia, Greece
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31
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Liu J, Zhang Y. Intratumor microbiome in cancer progression: current developments, challenges and future trends. Biomark Res 2022; 10:37. [PMID: 35642013 PMCID: PMC9153132 DOI: 10.1186/s40364-022-00381-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 05/01/2022] [Indexed: 11/29/2022] Open
Abstract
Cancer is a complicated disease attributed to multifactorial changes, which causes difficulties with treatment strategies. Various factors have been regarded as the main contributors, and infectious etiological factors have recently attracted interest. Several microbiomes contribute to carcinogenesis, cancer progression, and modulating cancer treatment by inducing cancerous epithelial cells and chronic inflammation. Most of our knowledge on the role of microbiota in tumor oncogenesis and clinical efficiency is associated with the intestinal microbiome. However, compelling evidence has also confirmed the contribution of the intratumor microbiome in cancer. Indeed, the findings of clinical tumor samples, animal models, and studies in vitro have revealed that many intratumor microbiomes promote tumorigenesis and immune evasion. In addition, the intratumor microbiome participates in regulating the immune response and even affects the outcomes of cancer treatment. This review summarizes the interplay between the intratumor microbiota and cancer, focusing on the contribution and mechanism of intratumor microbiota in cancer initiation, progression, and potential applications to cancer therapy.
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Affiliation(s)
- Jinyan Liu
- Biotherapy Center and Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yi Zhang
- Biotherapy Center and Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China.
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Safikhani Mahmoodzadeh A, Moazamian E, Shamsdin SA, Kaydani GA. Prevalence of Virulence Genes and Antigen Pattern in Helicobacter pylori-Infected Patients and the Level of Some Inflammatory Cytokines Compared with Non-infected Individuals. Jundishapur J Microbiol 2022; 15. [DOI: 10.5812/jjm-121144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 02/22/2022] [Accepted: 04/05/2022] [Indexed: 01/04/2025] Open
Abstract
Background: The worldwide prevalence of Helicobacter pylori is about 50%. This bacterium needs a number of virulence factors for pathogenesis. Objectives: This study aimed to determine the prevalence of virulence genes (ureB, cytotoxin-associated gene A [cagA], and vacuolating cytotoxin [vacA]), as well as the antigenic profile in H. pylori strains. Methods: Eighty-five patients with abdominal pain, including 46 H. pylori-positive and 39 H. pylori-negative cases, were enrolled in this study. The serum levels of interleukin (IL)-17F, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ) cytokines were measured by multiplex kits and flow cytometry. After molecular identification by the ureC gene, vacA, cagA, and ureB genes were detected by polymerase chain reaction (PCR). Finally, after antigenic extraction, the whole-cell protein was exhibited by sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS-PAGE). Results: The prevalence of vacA, ureB, and cagA genes were 91.3%, 67.39%, and 50%, respectively. The frequency of genes and cell surface antigens were not significantly different based on the gastritis severity (P > 0.05). IL-17F significantly (P = 0.046) increased in the presence of 19.5 kDa (outer membrane protein [OMP]). Moreover, the OMP antigen significantly enhanced immunoglobulin A (IgA; P = 0.013). In the presence of the 66-kDa (ureB) antigen, the serum level of IFN-γ increased (p = 0.041). Finally, the CagA protein led to increased IgG antibody levels (p = 0.027). Conclusions: Early detection of H. pylori infection can play a crucial role in managing it. Our results suggest that IL-17F, TNF-α, and IFN-γ cytokines could be diagnostic markers. However, further studies are required to fully investigate this suggestion.
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Shi Y, Zheng H, Wang M, Ding S. Influence of Helicobacter pylori infection on PD-1/PD-L1 blockade therapy needs more attention. Helicobacter 2022; 27:e12878. [PMID: 35112435 DOI: 10.1111/hel.12878] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/31/2021] [Accepted: 01/04/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVE The tumor microenvironment and tumor immunity are crucially involved in tumor therapy. Immune checkpoint inhibitors targeting PD-1/PD-L1 signal transduction have been widely used in tumor therapy and have shown ideal clinical efficacy. However, some kinds of cancers still do not respond to PD-1/PD-L1 blockade therapy effectively, including gastric cancer. The related factors should be explored. METHODS AND RESULTS This review summarizes the recent progression of understanding the influence of Helicobacter pylori infection on PD-1/PD-L1 blockade therapy. Current pieces of evidence have indicated that H. pylori infection might affect the curative effect of tumor therapy associating with the induced immunomodulation. CONCLUSION It is necessary to understand the overall integration of PD-1/PD-L1 blockade therapy, the tumor microenvironment, and H. pylori infection. Much attention on the influence of H. pylori infection on the efficacy of tumor immunotherapy should be paid.
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Affiliation(s)
- Yanyan Shi
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China
| | - Huiling Zheng
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Mopei Wang
- Department of Tumor Chemotherapy and Radiation Sickness, Peking University Third Hospital, Beijing, China
| | - Shigang Ding
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
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Yang H, Hu B. Immunological Perspective: Helicobacter pylori Infection and Gastritis. Mediators Inflamm 2022; 2022:2944156. [PMID: 35300405 PMCID: PMC8923794 DOI: 10.1155/2022/2944156] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 03/02/2022] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori is a spiral-shaped gram-negative bacterium. Its infection is mainly transmitted via oral-oral and fecal-oral routes usually during early childhood. It can achieve persistent colonization by manipulating the host immune responses, which also causes mucosal damage and inflammation. H. pylori gastritis is an infectious disease and results in chronic gastritis of different severity in near all patients with infection. It may develop from acute/chronic inflammation, chronic atrophic gastritis, intestinal metaplasia, dysplasia, and intraepithelial neoplasia, eventually to gastric cancer. This review attempts to cover recent studies which provide important insights into how H. pylori causes chronic inflammation and what the characteristic is, which will immunologically explain H. pylori gastritis.
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Affiliation(s)
- Hang Yang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bing Hu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Idowu S, Bertrand PP, Walduck AK. Homeostasis and Cancer Initiation: Organoids as Models to Study the Initiation of Gastric Cancer. Int J Mol Sci 2022; 23:2790. [PMID: 35269931 PMCID: PMC8911327 DOI: 10.3390/ijms23052790] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/23/2022] [Accepted: 02/25/2022] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer represents a significant disease burden worldwide. The factors that initiate cancer are not well understood. Chronic inflammation such as that triggered by H. pylori infection is the most significant cause of gastric cancer. In recent years, organoid cultures developed from human and animal adult stem cells have facilitated great advances in our understanding of gastric homeostasis. Organoid models are now being exploited to investigate the role of host genetics and bacterial factors on proliferation and DNA damage in gastric stem cells. The impact of a chronic inflammatory state on gastric stem cells and the stroma has been less well addressed. This review discusses what we have learned from the use of organoid models to investigate cancer initiation, and highlights questions on the contribution of the microbiota, chronic inflammatory milieu, and stromal cells that can now be addressed by more complex coculture models.
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Affiliation(s)
| | | | - Anna K. Walduck
- STEM College, RMIT University, Melbourne, VIC 3000, Australia; (S.I.); (P.P.B.)
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Araújo GRL, Marques HS, Santos MLC, da Silva FAF, da Brito BB, Correa Santos GL, de Melo FF. Helicobacter pylori infection: How does age influence the inflammatory pattern? World J Gastroenterol 2022; 28:402-411. [PMID: 35125826 PMCID: PMC8790560 DOI: 10.3748/wjg.v28.i4.402] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 06/21/2021] [Accepted: 01/13/2022] [Indexed: 02/06/2023] Open
Abstract
The inflammatory pattern during Helicobacter pylori (H. pylori) infection is changeable and complex. During childhood, it is possible to observe a predominantly regulatory response, evidenced by high concentrations of key cytokines for the maintenance of Treg responses such as TGF-β1 and IL-10, in addition to high expression of the transcription factor FOXP3. On the other hand, there is a predominance of cytokines associated with the Th1 and Th17 responses among H. pylori-positive adults. In the last few years, the participation of the Th17 response in the gastric inflammation against H. pylori infection has been highlighted due to the high levels of TGF-β1 and IL-17 found in this infectious scenario, and growing evidence has supported a close relationship between this immune response profile and unfavorable outcomes related to the infection. Moreover, this cytokine profile might play a pivotal role in the effectiveness of anti-H. pylori vaccines. It is evident that age is one of the main factors influencing the gastric inflammatory pattern during the infection with H. pylori, and understanding the immune response against the bacterium can assist in the development of alternative prophylactic and therapeutic strategies against the infection as well as in the comprehension of the pathogenesis of the outcomes related to that microorganism.
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Affiliation(s)
- Glauber Rocha Lima Araújo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Brazil
| | | | | | - Breno Bittencourt da Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
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Evaluation of Galectin-3 and CD19 in Helicobacter pylori patients infected with stomach cancer. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101520] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Ansari H, Tahmasebi-Birgani M, Bijanzadeh M. DNA vaccine containing Flagellin A gene induces significant immune responses against Helicobacter pylori infection: An in vivo study. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:796-804. [PMID: 34630957 PMCID: PMC8487603 DOI: 10.22038/ijbms.2021.54415.12227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 05/23/2021] [Indexed: 11/17/2022]
Abstract
Objective(s): Helicobacter pylori is one of the most prevalent human infectious agents that is directly involved in various upper digestive tract diseases. Although antibiotics-based therapy and proton pump inhibitors eradicate the bacteria mostly, their effectiveness has been declined recently due to emergence of antibiotic-resistant strains. Development of a DNA vaccine is a promising approach against bacterial pathogens. Genes encoding motility factors are promising immunogens to develop a DNA vaccine against H. pylori infection due to critical role of these genes in bacterial attachment and colonization within the gastric lumen. The present study aimed to synthesize a DNA vaccine construct based on the Flagellin A gene (flaA), the predominant flagellin subunit in H. pylori flagella. Materials and Methods: The coding sequence of flaA was amplified through PCR and sub-cloned in the pBudCE4.1 vector. The recombinant vector was introduced into the human dermal fibroblast cells, and its potency to express the flaA protein was analyzed using SDS-PAGE. The recombinant construct was intramuscularly (IM) injected into the mice, and the profiles of cytokines and immunoglobulins were measured using ELISA. Results: It has been found that flaA was successfully expressed in cells. Recombinant-vector also increased the serum levels of evaluated cytokines and immunoglobulins in mice. Conclusion: These findings showed that the pBudCE4.1-flaA construct was able to activate the immune responses. This study is the first step towards synthesis of recombinant-construct based on the flaA gene. Immunization with such construct may inhibit the H. pylori-associated infection; however, further experiments are urgent.
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Affiliation(s)
- Hossein Ansari
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Biotechnology, Islamic Azad University of Ahvaz, Ahvaz Branch, Ahvaz, Iran
| | - Maryam Tahmasebi-Birgani
- Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahdi Bijanzadeh
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Cullin N, Azevedo Antunes C, Straussman R, Stein-Thoeringer CK, Elinav E. Microbiome and cancer. Cancer Cell 2021; 39:1317-1341. [PMID: 34506740 DOI: 10.1016/j.ccell.2021.08.006] [Citation(s) in RCA: 299] [Impact Index Per Article: 74.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 08/05/2021] [Accepted: 08/13/2021] [Indexed: 12/14/2022]
Abstract
The human microbiome constitutes a complex multikingdom community that symbiotically interacts with the host across multiple body sites. Host-microbiome interactions impact multiple physiological processes and a variety of multifactorial disease conditions. In the past decade, microbiome communities have been suggested to influence the development, progression, metastasis formation, and treatment response of multiple cancer types. While causal evidence of microbial impacts on cancer biology is only beginning to be unraveled, enhanced molecular understanding of such cancer-modulating interactions and impacts on cancer treatment are considered of major scientific importance and clinical relevance. In this review, we describe the molecular pathogenic mechanisms shared throughout microbial niches that contribute to the initiation and progression of cancer. We highlight advances, limitations, challenges, and prospects in understanding how the microbiome may causally impact cancer and its treatment responsiveness, and how microorganisms or their secreted bioactive metabolites may be potentially harnessed and targeted as precision cancer therapeutics.
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Affiliation(s)
- Nyssa Cullin
- Microbiome and Cancer Division, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Camila Azevedo Antunes
- Microbiome and Cancer Division, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Ravid Straussman
- Department of Molecular Cell Biology, Weizmann Institute of Science, 234 Herzl Street, 7610001 Rehovot, Israel
| | - Christoph K Stein-Thoeringer
- Microbiome and Cancer Division, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
| | - Eran Elinav
- Microbiome and Cancer Division, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Immunology, Weizmann Institute of Science, 234 Herzl Street, 7610001 Rehovot, Israel.
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Gastric Microenvironment-A Partnership between Innate Immunity and Gastric Microbiota Tricks Helicobacter pylori. J Clin Med 2021; 10:jcm10153258. [PMID: 34362042 PMCID: PMC8347153 DOI: 10.3390/jcm10153258] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/17/2021] [Accepted: 07/21/2021] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) carcinogenicity depends on three major factors: bacterial virulence constituents, environmental factors and host's genetic susceptibility. The relationship between microenvironmental factors and H. pylori virulence factors are incontestable. H. pylori infection has a major impact on both gastric and colonic microbiota. The presence of non-H. pylori bacteria within the gastric ecosystem is particularly important since they might persistently act as an antigenic stimulus or establish a partnership with H. pylori in order to augment the subsequent inflammatory responses. The gastric ecosystem, i.e., microbiota composition in children with H. pylori infection is dominated by Streptoccocus, Neisseria, Rothia and Staphylococcus. The impairment of this ecosystem enhances growth and invasion of different pathogenic bacteria, further impairing the balance between the immune system and mucosal barrier. Moreover, altered microbiota due to H. pylori infection is involved in increasing the gastric T regulatory cells response in children. Since gastric homeostasis is defined by the partnership between commensal bacteria and host's immune system, this review is focused on how pathogen recognition through toll-like receptors (TLRs-an essential class of pathogen recognition receptors-PRRs) on the surface of macrophages and dendritic cells impact the immune response in the setting of H. pylori infection. Further studies are required for delineate precise role of bacterial community features and of immune system components.
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Afra LG, Afkhami H, Khaledi M, Fathi J, Taghadosi R, Hoseini MHM, Afra MG, Heidari M. Detection of H. pylori in tissues with benign prostatic hyperplasia isolates from hospitalized patient in Qom, Iran. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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González MF, Díaz P, Sandoval-Bórquez A, Herrera D, Quest AFG. Helicobacter pylori Outer Membrane Vesicles and Extracellular Vesicles from Helicobacter pylori-Infected Cells in Gastric Disease Development. Int J Mol Sci 2021; 22:ijms22094823. [PMID: 34062919 PMCID: PMC8124820 DOI: 10.3390/ijms22094823] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 02/08/2023] Open
Abstract
Extracellular vesicles (EVs) are cell-derived vesicles important in intercellular communication that play an essential role in host-pathogen interactions, spreading pathogen-derived as well as host-derived molecules during infection. Pathogens can induce changes in the composition of EVs derived from the infected cells and use them to manipulate their microenvironment and, for instance, modulate innate and adaptive inflammatory immune responses, both in a stimulatory or suppressive manner. Gastric cancer is one of the leading causes of cancer-related deaths worldwide and infection with Helicobacter pylori (H. pylori) is considered the main risk factor for developing this disease, which is characterized by a strong inflammatory component. EVs released by host cells infected with H. pylori contribute significantly to inflammation, and in doing so promote the development of disease. Additionally, H. pylori liberates vesicles, called outer membrane vesicles (H. pylori-OMVs), which contribute to atrophia and cell transformation in the gastric epithelium. In this review, the participation of both EVs from cells infected with H. pylori and H. pylori-OMVs associated with the development of gastric cancer will be discussed. By deciphering which functions of these external vesicles during H. pylori infection benefit the host or the pathogen, novel treatment strategies may become available to prevent disease.
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Affiliation(s)
- María Fernanda González
- Center for studies on Exercise, Metabolism and Cancer (CEMC), Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Faculty of Medicine, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago 8380453, Chile; (M.F.G.); (P.D.); (A.S.-B.); (D.H.)
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Paula Díaz
- Center for studies on Exercise, Metabolism and Cancer (CEMC), Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Faculty of Medicine, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago 8380453, Chile; (M.F.G.); (P.D.); (A.S.-B.); (D.H.)
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Alejandra Sandoval-Bórquez
- Center for studies on Exercise, Metabolism and Cancer (CEMC), Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Faculty of Medicine, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago 8380453, Chile; (M.F.G.); (P.D.); (A.S.-B.); (D.H.)
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Daniela Herrera
- Center for studies on Exercise, Metabolism and Cancer (CEMC), Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Faculty of Medicine, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago 8380453, Chile; (M.F.G.); (P.D.); (A.S.-B.); (D.H.)
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Andrew F. G. Quest
- Center for studies on Exercise, Metabolism and Cancer (CEMC), Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Faculty of Medicine, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago 8380453, Chile; (M.F.G.); (P.D.); (A.S.-B.); (D.H.)
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
- Corporación Centro de Estudios Científicos de las Enfermedades Crónicas (CECEC), Santiago 7680201, Chile
- Correspondence: ; Tel.: +56-2-29786832
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Abstract
Helicobacter pylori (H. pylori) represents one of the most widespread bacterial infections globally. Infection causes chronic gastritis and increases the risk of peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. The pioneering discovery of H. pylori by Marshall and Warren in the early 1980s has initiated fervent research into H. pylori as a pathogen ever since. This chapter aims to provide an overview of our understanding of H. pylori infection and its management, with a focus on current options for diagnosis, the challenges associated with H. pylori eradication, and the need for alternative therapeutic strategies based on furthering our understanding of host: H. pylori interactions.
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Affiliation(s)
| | - Sinéad M Smith
- Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
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Sanaei MJ, Shirzad H, Soltani A, Abdollahpour-Alitappeh M, Shafigh MH, Rahimian G, Mirzaei Y, Bagheri N. Up-regulated CCL18, CCL28 and CXCL13 Expression is Associated with the Risk of Gastritis and Peptic Ulcer Disease in Helicobacter Pylori infection. Am J Med Sci 2021; 361:43-54. [PMID: 32928496 DOI: 10.1016/j.amjms.2020.07.030] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 05/17/2020] [Accepted: 07/25/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) infection causes inflammation and increases the risk of developing peptic ulcer disease (PUD); however, the exact molecular mechanisms of PUD development remain unclear. The aim of this study was to investigate the expression of CCL18, CCL28, and CXCL13 in H. pylori-positive subjects in comparison with H. pylori-negative subjects, and to determine its association with different clinical outcomes and virulence factors. METHODS In total, 55 H. pylori-positive subjects with gastritis, 47 H. pylori-positive subjects with PUD, and 48 H. pylori-negative subjects were enrolled in this study. CCL18, CCL28, and CXCL13 expression were determined using real time polymerase chain reaction (PCR). The virulence factors of H. pylori such as cytotoxin-associated gene A (cagA), outer inflammatory protein A (oipA), blood group antigen-binding adhesin (babA), and vacuolating cytotoxin A (VacA) genes were evaluated using PCR. RESULTS CCL18, CCL28, and CXCL13 expression in H. pylori-positive subjects were significantly higher than H. pylori-negative subjects. CCL18 and CXCL13 expression in H. pylori-positive subjects with oipA+ and babA2+were significantly higher than H. pylori-positive subjects with oipA¯ and babA2¯. CCL18 and CXCL13 expression were found to be significantly elevated in H. pylori-positive subjects with gastritis compared with H. pylori-positive subjects with PUD. CCL28 expression was significantly higher in H. pylori-positive subjects with PUD compared with H. pylori-positive subjects with gastritis. CONCLUSIONS The increased of CCL18 and CXCL13 may be involved in the pathogenesis of H. pylori-associated gastritis, while the increased of CCL28 may be involved in the pathogenesis of H. pylori-associated PUD.
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Affiliation(s)
- Mohammad-Javad Sanaei
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Hedayatollah Shirzad
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | - Amin Soltani
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | | | - Mohammad-Hadi Shafigh
- Department of Internal Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Ghorbanali Rahimian
- Department of Internal Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Yousef Mirzaei
- Department of Biology, Faculty of Sciences, Soran University, Soran, Kurdistan Region, Iraq
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
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Azadegan-Dehkordi F, Shirzad H, Ahmadi R, Bashash D, Abdollahpour-Alitappeh M, Luzza F, Larussa T, Nahid-Samiei M, Rahimian G, Shafigh MH, Bagheri N. Increased Indoleamine 2, 3-Dioxygenase expression modulates Th1/Th17/Th22 and Treg pathway in humans with Helicobacter Pylori-Infected gastric mucosa. Hum Immunol 2021; 82:46-53. [PMID: 33127161 PMCID: PMC8414194 DOI: 10.1016/j.humimm.2020.10.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 09/18/2020] [Accepted: 10/16/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND PURPOSE Indoleamine 2, 3- dioxygenase (IDO) plays an importantrole in immunosuppressive pathway, as inhibits responsesof T cells and promotes immune tolerance. Host responsetoHelicobacter pylori (H. pylori) is involved in the infection persistenceand it is also associatedwith different clinical outcomes. The aim of this study was to investigate the role of IDO in H. pylori-infected patients with gastritis diseases and peptic ulcer diseases (PUD) through the assessment of the relationship among IDO protein expression and the numbers of T helper (Th)-1, Th17, Th22, and T regulator (Treg) cells. MATERIALS AND METHODS Antrum biopsy was obtained from H. pylori-negative patients (n = 48) and H. pylori-positive subjects (55 patients with gastritis and 47 patients with PUD), for performing H. pylori status and histopathological assessments. IDO protein expression was evaluated by Western blotting. RESULTS IDO protein expression was significantly higher in gastric biopsies from H. pylori-positive subjects compared to the H. pylori-negative subjects, and also in H. pylori-positive subjects with gastritis disease compared to H. pylori-positive subjects with PUD. Moreover, in H. pylori-positive subjects, a positive correlation was observed between IDO protein expression and the frequency of Treg cells. In addition, a negative correlation was observed between IDO protein expression and the number of Th1, Th17, and Th22. CONCLUSION Increased IDO protein expression is able to change the number of Th1, Th17, Th22, and Treg cells and these changes are possibly associated with an increase in the risk of PUD development in H. pylori-infected patients.
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Affiliation(s)
- Fateme Azadegan-Dehkordi
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Hedayatollah Shirzad
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Reza Ahmadi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Francesco Luzza
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy
| | - Tiziana Larussa
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy
| | - Mahboobeh Nahid-Samiei
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Ghorbanali Rahimian
- Department of Internal Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad-Hadi Shafigh
- Department of Internal Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
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Infiltration of Immunoinflammatory Cells and Related Chemokine/Interleukin Expression in Different Gastric Immune Microenvironments. J Immunol Res 2020; 2020:2450569. [PMID: 33426088 PMCID: PMC7774301 DOI: 10.1155/2020/2450569] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 12/07/2020] [Accepted: 12/12/2020] [Indexed: 01/23/2023] Open
Abstract
Gastric mucosal immune microenvironment plays an important role in the occurrence and development of diseases such as inflammation and cancer. In the present study, single-sample gene set enrichment analysis (ssGSEA) was used to evaluate the expression of cytokines and the degree of immune cell infiltration in four different gastric mucosa tissues from normal gastric mucosa, simple gastritis, and atrophic gastritis to gastric cancer. Here, we show the immune microenvironments of these four gastric mucosae were significantly different. From inflammation to gastric cancer, most immunoinflammatory cells showed a downward trend such as central memory CD4 T cell. Instead, several cells showed an upward trend such as macrophage. Additionally, we found some chemokines/interleukins were illustrated to be low expressed (or highly expressed) in precancerous stage and highly expressed (or low expressed) in postcancerous stage, which demonstrated an opposite expression characteristic in pre-/postcancerous stage.
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Xie J, Wen J, Chen C, Luo M, Hu B, Wu D, Ye J, Lin Y, Ning L, Ning Y, Li Y. Notch 1 Is Involved in CD4 + T Cell Differentiation Into Th1 Subtype During Helicobacter pylori Infection. Front Cell Infect Microbiol 2020; 10:575271. [PMID: 33224898 PMCID: PMC7667190 DOI: 10.3389/fcimb.2020.575271] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/24/2020] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori infection induces CD4+ T differentiation cells into IFN-γ-producing Th1 cells. However, the details of mechanism underlying this process remain unclear. Notch signal pathway has been reported to regulate the differentiation of CD4+ T cells into Th1 subtype in many Th1-mediated inflammatory disorders but not yet in H. pylori infection. In the present study, the mRNA expression pattern of CD4+ T cells in H. pylori-infected patients differed from that of healthy control using Human Signal Transduction Pathway Finder RT2 Profiler PCR Array, and this alteration was associated with Notch signal pathway, as analyzed by Bioinformation. Quantitative real-time PCR showed that the mRNA expression of Notch1 and its target gene Hes-1 in CD4+ T cells of H. pylori-infected individuals increased compared with the healthy controls. In addition, the mRNA expression of Th1 master transcription factor T-bet and Th1 signature cytokine IFN-γ was both upregulated in H. pylori-infected individuals and positively correlated with Notch1 expression. The increased protein level of Notch1 and IFN-γ were also observed in H. pylori-infected individuals confirmed by flow cytometry and ELISA. In vitro, inhibition of Notch signaling decreased the mRNA expression of Notch1, Hes-1, T-bet, and IFN-γ, and reduced the protein levels of Notch1 and IFN-γ and the secretion of IFN-γ in CD4+ T cells stimulated by H. pylori. Collectively, this is the first evidence that Notch1 is upregulated and involved in the differentiation of Th1 cells during H. pylori infection, which will facilitate exploiting Notch1 as a therapeutic target for the control of H. pylori infection.
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Affiliation(s)
- Jinling Xie
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.,Affiliated Xinhui People's Hospital, Southern Medical University, Jiangmen, China
| | - Junjie Wen
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Chuxi Chen
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Meiqun Luo
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Bingxin Hu
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Danlin Wu
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Jianbin Ye
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yanqing Lin
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Lijun Ning
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yunshan Ning
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yan Li
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
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Algood HMS. T Cell Cytokines Impact Epithelial Cell Responses during Helicobacter pylori Infection. THE JOURNAL OF IMMUNOLOGY 2020; 204:1421-1428. [PMID: 32152211 DOI: 10.4049/jimmunol.1901307] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 12/08/2019] [Indexed: 12/24/2022]
Abstract
The goal of this Brief Review is to highlight literature that demonstrates how cytokines made by T lymphocytes impact the gastric epithelium, especially during Helicobacter pylori infection. These cytokines effect many of the diverse functions of the epithelium and the epithelium's interactions with H. pylori The focal point of this Brief Review will be on how T cell cytokines impact antimicrobial function and barrier function and how T cell cytokines influence the development and progression of cancer. Furthermore, the modulation of epithelial-derived chemokines by H. pylori infection will be discussed.
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Affiliation(s)
- Holly M Scott Algood
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, TN 37212; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212; and Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37212
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50
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Chen J, Zhong Y, Liu Y, Tang C, Zhang Y, Wei B, Chen W, Liu M. Parenteral immunization with a cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) adjuvanted Helicobacter pylori vaccine induces protective immunity against H. pylori infection in mice. Hum Vaccin Immunother 2020; 16:2849-2854. [PMID: 32298215 PMCID: PMC7733891 DOI: 10.1080/21645515.2020.1744364] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 03/11/2020] [Indexed: 02/06/2023] Open
Abstract
Under the trend of antibiotic resistance of H. pylori leading to the decrease of eradication rate, the development of a vaccine is the best choice to fight against H. pylori. In this study, we attempted to reduce the amounts of required antigens by using three different parenteral routes of immunization and an adjuvant cGAMP (cyclic guanosine monophosphate-adenosine monophosphate) to enhance the immunogenicity of the vaccine candidate. The immune protection and post-challenge immune responses were assessed and compared in mice immunized with recombinant Helicobacter pylori urease A, urease B, and neutrophil-activating protein adjuvanted with cGAMP. The gastric mucosal colonization by H. pylori was significantly reduced in mice immunized by intranasal and, to a less degree, subcutaneous route, but not by intramuscular route. All immunized mice, regardless of the route of immunization, displayed significant, but comparable, increases in antigen-specific serum IgG and mucosal IgA responses 5 weeks post-challenge. The magnitude of the vaccine-induced protection appeared to be associated with the level of antigen-specific Th1 and particularly Th17 responses, as IL-17 responses were only detected in intranasally immunized mice. Taken together, we explored and confirmed the possibility of using a novel adjuvant (cGAMP) to induce significant protective immunity with 10% of oral vaccine antigen dosage through parenteral immunization, especially intranasal immunization. This may provide an alternative approach to oral immunization for the development of effective H. pylori vaccines.
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Affiliation(s)
- Jing Chen
- National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), Beijing, China
| | - Youxiu Zhong
- National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), Beijing, China
| | - Yu Liu
- National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), Beijing, China
| | - Chongfa Tang
- National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), Beijing, China
| | - Yanbin Zhang
- National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), Beijing, China
| | - Bo Wei
- JOINN Laboratories CA Inc., San Francisco, CA, USA
| | - Wangxue Chen
- Human Health Therapeutics (HHT) Research Center, National Research Council Canada, Ottawa, ON, Canada
| | - Meiying Liu
- National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), Beijing, China
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