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Brackman LC, Jung MS, Ogaga EI, Joshi N, Wroblewski LE, Piazuelo MB, Peek RM, Choksi YA, Algood HMS. IL-17RA-Mediated Epithelial Cell Activity Prevents Severe Inflammatory Response to Helicobacter pylori Infection. Immunohorizons 2024; 8:339-353. [PMID: 38639570 PMCID: PMC11066722 DOI: 10.4049/immunohorizons.2300078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 03/21/2024] [Indexed: 04/20/2024] Open
Abstract
Helicobacter pylori is a Gram-negative pathogen that colonizes the stomach, induces inflammation, and drives pathological changes in the stomach tissue, including gastric cancer. As the principal cytokine produced by Th17 cells, IL-17 mediates protective immunity against pathogens by inducing the activation and mobilization of neutrophils. Whereas IL-17A is largely produced by lymphocytes, the IL-17 receptor is expressed in epithelial cells, fibroblasts, and hematopoietic cells. Loss of the IL-17RA in mice results in impaired antimicrobial responses to extracellular bacteria. In the context of H. pylori infection, this is compounded by extensive inflammation in Il17ra-/- mice. In this study, Foxa3creIl17rafl/fl (Il17raΔGI-Epi) and Il17rafl/fl (control) mice were used to test the hypothesis that IL-17RA signaling, specifically in epithelial cells, protects against severe inflammation after H. pylori infection. The data indicate that Il17raΔGI-Epi mice develop increased inflammation compared with controls. Despite reduced Pigr expression, levels of IgA increased in the gastric wash, suggesting significant increase in Ag-specific activation of the T follicular helper/B cell axis. Gene expression analysis of stomach tissues indicate that both acute and chronic responses are significantly increased in Il17raΔGI-Epi mice compared with controls. These data suggest that a deficiency of IL-17RA in epithelial cells is sufficient to drive chronic inflammation and hyperactivation of the Th17/T follicular helper/B cell axis but is not required for recruitment of polymorphonuclear neutrophils. Furthermore, the data suggest that fibroblasts can produce chemokines in response to IL-17 and may contribute to H. pylori-induced inflammation through this pathway.
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Affiliation(s)
- Lee C. Brackman
- Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN
- Division of Infectious Disease, Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Matthew S. Jung
- Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN
- Division of Infectious Disease, Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Eseoghene I. Ogaga
- Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN
| | - Nikhita Joshi
- Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN
- Vanderbilt University, School of Biological Sciences, Nashville, TN
| | - Lydia E. Wroblewski
- Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - M. Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Richard M. Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Yash A. Choksi
- Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN
- Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Holly M. Scott Algood
- Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN
- Division of Infectious Disease, Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN
- Vanderbilt Institute of Infection, Immunity, and Inflammation, Vanderbilt University Medical Center, Nashville, TN
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2
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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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3
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Francis JE, Skakic I, Majumdar D, Taki AC, Shukla R, Walduck A, Smooker PM. Solid Lipid Nanoparticles Delivering a DNA Vaccine Encoding Helicobacter pylori Urease A Subunit: Immune Analyses before and after a Mouse Model of Infection. Int J Mol Sci 2024; 25:1076. [PMID: 38256149 PMCID: PMC10816323 DOI: 10.3390/ijms25021076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/08/2024] [Accepted: 01/13/2024] [Indexed: 01/24/2024] Open
Abstract
In this study, novel solid lipid particles containing the adjuvant lipid monophosphoryl lipid A (termed 'SLN-A') were synthesised. The SLN-A particles were able to efficiently bind and form complexes with a DNA vaccine encoding the urease alpha subunit of Helicobacter pylori. The resultant nanoparticles were termed lipoplex-A. In a mouse model of H. pylori infection, the lipoplex-A nanoparticles were used to immunise mice, and the resultant immune responses were analysed. It was found that the lipoplex-A vaccine was able to induce high levels of antigen-specific antibodies and an influx of gastric CD4+ T cells in vaccinated mice. In particular, a prime with lipoplex-A and a boost with soluble UreA protein induced significantly high levels of the IgG1 antibody, whereas two doses of lipoplex-A induced high levels of the IgG2c antibody. In this study, lipoplex-A vaccination did not lead to a significant reduction in H. pylori colonisation in a challenge model; however, these results point to the utility of the system for delivering DNA vaccine-encoded antigens to induce immune responses and suggest the ability to tailor those responses.
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Affiliation(s)
- Jasmine E. Francis
- School of Science, RMIT University, 264 Plenty Road, Bundoora, VIC 3083, Australia; (J.E.F.); (I.S.); (D.M.); (R.S.); (A.W.)
| | - Ivana Skakic
- School of Science, RMIT University, 264 Plenty Road, Bundoora, VIC 3083, Australia; (J.E.F.); (I.S.); (D.M.); (R.S.); (A.W.)
| | - Debolina Majumdar
- School of Science, RMIT University, 264 Plenty Road, Bundoora, VIC 3083, Australia; (J.E.F.); (I.S.); (D.M.); (R.S.); (A.W.)
| | - Aya C. Taki
- Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, VIC 3010, Australia;
| | - Ravi Shukla
- School of Science, RMIT University, 264 Plenty Road, Bundoora, VIC 3083, Australia; (J.E.F.); (I.S.); (D.M.); (R.S.); (A.W.)
| | - Anna Walduck
- School of Science, RMIT University, 264 Plenty Road, Bundoora, VIC 3083, Australia; (J.E.F.); (I.S.); (D.M.); (R.S.); (A.W.)
| | - Peter M. Smooker
- School of Science, RMIT University, 264 Plenty Road, Bundoora, VIC 3083, Australia; (J.E.F.); (I.S.); (D.M.); (R.S.); (A.W.)
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4
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Wang Y, Yu B, Luo Y, Zheng P, Mao X, Huang Z, Yu J, Luo J, Yan H, Wu A, He J. Interferon-λ3 alleviates intestinal epithelium injury induced by porcine rotavirus in mice. Int J Biol Macromol 2023; 240:124431. [PMID: 37060970 DOI: 10.1016/j.ijbiomac.2023.124431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 03/15/2023] [Accepted: 04/09/2023] [Indexed: 04/17/2023]
Abstract
Interferons are a group of glycoproteins that are expressed in various cell types in their inflammatory responses to infections. In this study, we explored the protective effects of porcine interferon-λ3 (PIFN-λ3) on intestinal inflammation and injury in mice induced by porcine rotavirus (PRV). BALB/c mice were administrated by PIFN-λ3 or phosphate buffer solution (PBS) for three days prior to PRV infection. We show that PRV infection caused acute inflammatory responses in mice, as indicated by increases in serum concentrations of inflammatory cytokines such as the interlukin-1β (IL-1β), interlukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) (P < 0.05). However, PIFN-λ3 administration not only decreased their concentrations but also elevated the concentrations of immunoglobulin (Ig) M and IgG in the PRV challenged mice (P < 0.05). PRV infection significantly decreased the jejunal villus height and the ratio of villus height to crypt depth (V/C); however, PIFN-λ3 treatment significantly elevated the villus height and the abundance of tight junction protein ZO-1 in the jejunum (P < 0.05). Moreover, PIFN-λ3 decreased the replication of PRV in the jejunal epithelium, but significantly increased the abundance of sIgA and the activities of maltase and sucrase in the PRV-challenged mice (P < 0.05). Interestingly, PIFN-λ3 elevated the expression levels of sodium/glucose cotransporter 1 (SGLT1) and mucin 2 (MUC2) in the PRV-challenged mice (P < 0.05). Moreover, PIFN-λ3 significantly increased the expression levels of IL-10, signal transducer and activator of transcription 1 (STAT1), and critical interferon-stimulated genes such as the 2'-5' oligoadenylate synthetase-like 1 (OASL1), interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and radical S-adenosyl methionine domain containing 2 (RSAD2) in the jejunum upon PRV infection (P < 0.05). The anti-virus and anti-inflammatory effect of PIFN-λ3 should make it an attractive candidate to prevent various pathogen-induced bowel diseases.
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Affiliation(s)
- Yuhan Wang
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan Province 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, Sichuan Province 611130, PR China
| | - Bing Yu
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan Province 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, Sichuan Province 611130, PR China
| | - Yuheng Luo
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan Province 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, Sichuan Province 611130, PR China
| | - Ping Zheng
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan Province 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, Sichuan Province 611130, PR China
| | - Xiangbing Mao
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan Province 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, Sichuan Province 611130, PR China
| | - Zhiqing Huang
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan Province 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, Sichuan Province 611130, PR China
| | - Jie Yu
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan Province 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, Sichuan Province 611130, PR China
| | - Junqiu Luo
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan Province 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, Sichuan Province 611130, PR China
| | - Hui Yan
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan Province 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, Sichuan Province 611130, PR China
| | - Aimin Wu
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan Province 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, Sichuan Province 611130, PR China
| | - Jun He
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan Province 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, Sichuan Province 611130, PR China.
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5
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Sijmons D, Guy AJ, Walduck AK, Ramsland PA. Helicobacter pylori and the Role of Lipopolysaccharide Variation in Innate Immune Evasion. Front Immunol 2022; 13:868225. [PMID: 35634347 PMCID: PMC9136243 DOI: 10.3389/fimmu.2022.868225] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 04/04/2022] [Indexed: 11/30/2022] Open
Abstract
Helicobacter pylori is an important human pathogen that infects half the human population and can lead to significant clinical outcomes such as acute and chronic gastritis, duodenal ulcer, and gastric adenocarcinoma. To establish infection, H. pylori employs several mechanisms to overcome the innate and adaptive immune systems. H. pylori can modulate interleukin (IL) secretion and innate immune cell function by the action of several virulence factors such as VacA, CagA and the type IV secretion system. Additionally, H. pylori can modulate local dendritic cells (DC) negatively impacting the function of these cells, reducing the secretion of immune signaling molecules, and influencing the differentiation of CD4+ T helper cells causing a bias to Th1 type cells. Furthermore, the lipopolysaccharide (LPS) of H. pylori displays a high degree of phase variation and contains human blood group carbohydrate determinants such as the Lewis system antigens, which are proposed to be involved in molecular mimicry of the host. Lastly, the H. pylori group of outer membrane proteins such as BabA play an important role in attachment and interaction with host Lewis and other carbohydrate antigens. This review examines the various mechanisms that H. pylori utilises to evade the innate immune system as well as discussing how the structure of the H. pylori LPS plays a role in immune evasion.
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Affiliation(s)
- Daniel Sijmons
- School of Science, RMIT University, Melbourne, VIC, Australia
| | - Andrew J. Guy
- School of Science, RMIT University, Melbourne, VIC, Australia
- ZiP Diagnostics, Collingwood, VIC, Australia
| | - Anna K. Walduck
- School of Science, RMIT University, Melbourne, VIC, Australia
| | - Paul A. Ramsland
- School of Science, RMIT University, Melbourne, VIC, Australia
- Department of Immunology, Monash University, Melbourne, VIC, Australia
- Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia
- *Correspondence: Paul A. Ramsland,
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6
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Xie W, Zhao W, Zou Z, Kong L, Yang L. Oral multivalent epitope vaccine, based on UreB, HpaA, CAT, and LTB, for prevention and treatment of Helicobacter pylori infection in C57BL / 6 mice. Helicobacter 2021; 26:e12807. [PMID: 33847026 DOI: 10.1111/hel.12807] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 03/19/2021] [Accepted: 03/26/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND As the resistance of Helicobacter pylori to traditional triple therapy is gradually revealed, an increasing number of people are focusing on vaccine treatments for H. pylori infection. Epitope vaccines are a promising strategy for the treatment of H. pylori infection, and multivalent vaccines will be more effective than monovalent vaccines. MATERIALS AND METHODS In this study, we designed a multivalent vaccine named LHUC, which consists of the adjuvant LTB as well as three Th cell epitopes (HpaA154-171 , UreB237-251, and UreB546-561 ) and five B-cell epitopes (UreB349-363 , UreB327-334 , CAT394-405 , CAT387-397, and HpaA132-141 ) from UreB, HpaA, and catalase. In BALB/c mice, the specificity and immunogenicity of the fusion peptide LHUC and the neutralization of H. pylori urease and catalase by the specific IgG elicited by LHUC were evaluated. The preventive and therapeutic effects of LHUC were evaluated in C57BL/6 mice infected with H. pylori. RESULTS The results showed that compared with LTB and PBS, LHUC induced specific IgG and IgA antibody production in mice, and IgG antibodies significantly inhibited the H. pylori urease and catalase activities in vitro. Additionally, by detecting the levels of IFN-γ, IL-4, and IL-17 in lymphocyte supernatants, we proved that LHUC could activate Th1, Th2, and Th17 mixed T-cell immune responses in vivo. Finally, a C57BL/6 mouse model of gastric infection with H. pylori was established. The results showed that compared with the effects of LTB and PBS, the prevention and treatment effects of oral inoculation with LHUC significantly inhibited bacterial colonization. CONCLUSIONS In conclusion, LHUC, a multivalent vaccine based on multiple H. pylori antigens, is a promising and safe vaccine that can effectively reduce the colonization of H. pylori in the stomach.
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Affiliation(s)
- Wenwei Xie
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
| | - Wenfeng Zhao
- Department of Biochemistry, China Pharmaceutical university, Nanjing, China
| | - Ziling Zou
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
| | - Lingyi Kong
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
| | - Lei Yang
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
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7
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Gong Y, Jin X, Yuan B, Lv Y, Yan G, Liu M, Xie C, Liu J, Tang Y, Gao H, Zhu Y, Huang Y, Wang W. G Protein-Coupled Receptor 109A Maintains the Intestinal Integrity and Protects Against ETEC Mucosal Infection by Promoting IgA Secretion. Front Immunol 2021; 11:583652. [PMID: 33488584 PMCID: PMC7821714 DOI: 10.3389/fimmu.2020.583652] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 12/03/2020] [Indexed: 12/15/2022] Open
Abstract
Several studies have reported an intricate link between the G protein-coupled receptor 109A (GPR109A) and intestinal health. Upon activation, induced by butyric acid and β-hydroxybutyric acid, GPR109A regulates the expression of tight junction proteins, exerts anti-inflammatory effects, and maintains the integrity of the intestinal barrier. However, its function and the mechanism of action in combating the infection caused by exogenous pathogenic microorganisms remain unclear. This study established an animal model of infection by oral enterotoxigenic Escherichia coli (ETEC) gavage to examine the underlying mechanism(s) and protective effects of GPR109A on the intestinal tract. Experimental GPR109A-/-and GPR109A+/+ mice were orally administered with 1 × 109 colony-forming units (CFUs) of ETEC, and changes in body weight were then observed. The colonization and translocation of ETEC in the intestine were detected by the plate counting method. The expression of tight junction proteins and the levels of inflammatory factors and secretory IgA (SIgA) in the intestine were detected by quantitative real-time polymerase chain reaction (q-PCR), western blotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry. The results demonstrated that GPR109A-/-mice were more susceptible to ETEC infection, showing more severe inflammatory reactions and intestinal damage. Moreover, the secretion of IgA in the intestinal tract of GPR109A+/+ mice was significantly increased after ETEC infection, whereas the IgA levels in GPR109A-/-mice did not change significantly. We added 5 g/L sodium butyrate to the drinking water of all mice. The GPR109A+/+ mice were protected against ETEC infection and no effect was observed in GPR109A-/-mice. Similarly, sodium butyrate increased the SIgA content in the gut of the GPR109A+/+ mice and no effect was observed in GPR109A-/-mice. In conclusion, activated GPR109A is effective against the colonization and translocation of ETEC in the gut and maintains the integrity of the intestinal barrier, possibly by promoting the secretion of intestinal IgA.
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Affiliation(s)
- Yuhong Gong
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China.,Laboratory Animal Center of Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xinxin Jin
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China.,Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, China
| | - Boyu Yuan
- Department of Pharmacology, College of Basic Medical Science, Jilin University, Changchun, China
| | - Yantao Lv
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China
| | - Guangmou Yan
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Mingming Liu
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China.,Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, China
| | - Changxin Xie
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Juxiong Liu
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yimei Tang
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China
| | - Hongyan Gao
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China
| | - Yufeng Zhu
- Laboratory Animal Center of Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanhua Huang
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China
| | - Wei Wang
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China.,Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, China
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8
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FitzPatrick RD, Kennedy MHE, Lawrence KM, Gauthier CM, Moeller BE, Robinson AN, Reynolds LA. Littermate-Controlled Experiments Reveal Eosinophils Are Not Essential for Maintaining Steady-State IgA and Demonstrate the Influence of Rearing Conditions on Antibody Phenotypes in Eosinophil-Deficient Mice. Front Immunol 2020; 11:557960. [PMID: 33178185 PMCID: PMC7593696 DOI: 10.3389/fimmu.2020.557960] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 09/10/2020] [Indexed: 12/18/2022] Open
Abstract
Conflicting data has emerged regarding a role for eosinophils in IgA production, with some reports that eosinophils support both secretory and circulating IgA levels during homeostasis. Previous studies have compared antibody levels between wildtype and eosinophil-deficient mice, but these mice were obtained from different commercial vendors and/or were not littermates. Thus, the possibility remains that extrinsic environmental factors, rather than an intrinsic lack of eosinophils, are responsible for the reports of reduced IgA in eosinophil-deficient mice. Here we used wild-type and eosinophil-deficient (ΔdblGATA) mice that were purchased from a single vendor, subsequently bred in-house and either co-housed as adults, co-reared from birth or raised as littermates. We found no differences in the levels of secretory IgA or in the numbers of small intestinal IgA-producing plasma cells between wild-type and ΔdblGATA mice, demonstrating that under controlled steady-state conditions eosinophils are not essential for the maintenance of secretory IgA in the intestinal tract. While we found that levels of IgM and IgE were significantly elevated in the serum of ΔdblGATA mice compared to co-reared or co-housed wild-type mice, no significant differences in these or other circulating antibody isotypes were identified between genotypes in littermate-controlled experiments. Our results demonstrate that eosinophils are not required to maintain secretory or circulating IgA production and the absence of eosinophils does not impact circulating IgG1, IgG2b, IgM, or IgE levels during homeostasis. These findings emphasize the importance of optimally controlling rearing and housing conditions throughout life between mice of different genotypes.
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Affiliation(s)
- Rachael D FitzPatrick
- Reynolds Laboratory, Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
| | - Mia H E Kennedy
- Reynolds Laboratory, Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
| | - Katherine M Lawrence
- Reynolds Laboratory, Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
| | - Courtney M Gauthier
- Reynolds Laboratory, Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
| | - Brandon E Moeller
- Reynolds Laboratory, Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
| | - Andrew N Robinson
- Reynolds Laboratory, Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
| | - Lisa A Reynolds
- Reynolds Laboratory, Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
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9
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Wang W, Zhou X, Cui F, Shi C, Wang Y, Men Y, Zhao W, Zhao J. Proteomic Analysis on Exosomes Derived from Patients' Sera Infected with Echinococcus granulosus. THE KOREAN JOURNAL OF PARASITOLOGY 2019; 57:489-497. [PMID: 31715689 PMCID: PMC6851256 DOI: 10.3347/kjp.2019.57.5.489] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 09/15/2019] [Indexed: 12/25/2022]
Abstract
Cystic echinococcosis (CE), a zoonotic disease caused by Echinococcus granulosus at the larval stage, predominantly develops in the liver and lungs of intermediate hosts and eventually results in organ malfunction or even death. The interaction between E. granulosus and human body is incompletely understood. Exosomes are nanosized particles ubiquitously present in human body fluids. Exosomes carry biomolecules that facilitate communication between cells. To the best of our knowledge, the role of exosomes in patients with CE is not reported. Here, we isolated exosomes from the sera of patients with CE (CE-exo) and healthy donors and subjected them to liquid chromatography-tandem mass spectrometry analysis. Proteomic analysis identified 49 proteins specifically expressed in CE-exo, including 4 proteins of parasitic origin. The most valuable parasitic proteins included tubulin alpha-1C chain and histone H4. And 8 proteins were differentially regulated in CE-exo (fold change>1.5), as analyzed with bioinformatic methods such as annotation and functional enrichment analyses. These findings may improve our understanding about the interaction between E. granulosus and human body, and may contribute to the diagnosis and prevention of CE.
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Affiliation(s)
- Wen Wang
- School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, China
| | - Xiaojing Zhou
- College of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, China
| | - Fang Cui
- School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, China
| | - Chunli Shi
- School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, China
| | - Yulan Wang
- College of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, China
| | - Yanfei Men
- College of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, China
| | - Wei Zhao
- School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, China.,The Medical Scientific Institute of Ningxia, Yinchuan 750004, China.,Center of Scientific Technology, Ningxia Medical University, Yinchuan 750004, China
| | - Jiaqing Zhao
- School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, China.,The Medical Scientific Institute of Ningxia, Yinchuan 750004, China.,Center of Scientific Technology, Ningxia Medical University, Yinchuan 750004, China
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10
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Gastric Cancer in the Era of Immune Checkpoint Blockade. JOURNAL OF ONCOLOGY 2019; 2019:1079710. [PMID: 31662748 PMCID: PMC6778883 DOI: 10.1155/2019/1079710] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Accepted: 08/22/2019] [Indexed: 12/24/2022]
Abstract
Gastric cancer (GC) is one of the most important malignancies worldwide because of its high incidence and mortality. The very low survival rates are mainly related to late diagnosis and limited treatment options. GC is the final clinical outcome of a stepwise process that starts with a chronic and sustained inflammatory reaction mounted in response to Helicobacter pylori infection. The bacterium modulates innate and adaptive immunity presumably as part of the strategies to survive, which favors the creation of an immunosuppressive microenvironment that ultimately facilitates GC progression. T-cell exhaustion, which is characterized by elevated expression of immune checkpoint (IC) proteins, is one of the most salient manifestations of immunosuppressive microenvironments. It has been consistently demonstrated that the tumor-immune microenvironment(TIME)‐exhausted phenotype can be reverted by blocking ICs with monoclonal antibodies. Although these therapies are associated with long-lasting response rates, only a subset of patients derive clinical benefit, which varies according to tumor site. The search for biomarkers to predict the response to IC inhibition is a matter of intense investigation as this may contribute to maximize disease control, reduce side effects, and minimize cost. The approval of pembrolizumab for its use in GC has rocketed immuno-oncology research in this cancer type. In this review, we summarize the current knowledge centered around the immune contexture and recent findings in connection with IC inhibition in GC.
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11
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Liu C, Luo J, Xue RY, Guo L, Nie L, Li S, Ji L, Ma CJ, Chen DQ, Miao K, Zou QM, Li HB. The mucosal adjuvant effect of plant polysaccharides for induction of protective immunity against Helicobacter pylori infection. Vaccine 2019; 37:1053-1061. [DOI: 10.1016/j.vaccine.2018.12.066] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 12/22/2018] [Accepted: 12/31/2018] [Indexed: 12/26/2022]
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12
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Natural Secretory Immunoglobulins Promote Enteric Viral Infections. J Virol 2018; 92:JVI.00826-18. [PMID: 30232191 DOI: 10.1128/jvi.00826-18] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 09/05/2018] [Indexed: 12/27/2022] Open
Abstract
Noroviruses are enteric pathogens causing significant morbidity, mortality, and economic losses worldwide. Secretory immunoglobulins (sIg) are a first line of mucosal defense against enteric pathogens. They are secreted into the intestinal lumen via the polymeric immunoglobulin receptor (pIgR), where they bind to antigens. However, whether natural sIg protect against norovirus infection remains unknown. To determine if natural sIg alter murine norovirus (MNV) pathogenesis, we infected pIgR knockout (KO) mice, which lack sIg in mucosal secretions. Acute MNV infection was significantly reduced in pIgR KO mice compared to controls, despite increased MNV target cells in the Peyer's patch. Natural sIg did not alter MNV binding to the follicle-associated epithelium (FAE) or crossing of the FAE into the lymphoid follicle. Instead, naive pIgR KO mice had enhanced levels of the antiviral inflammatory molecules interferon gamma (IFN-γ) and inducible nitric oxide synthase (iNOS) in the ileum compared to controls. Strikingly, depletion of the intestinal microbiota in pIgR KO and control mice resulted in comparable IFN-γ and iNOS levels, as well as MNV infectious titers. IFN-γ treatment of wild-type (WT) mice and neutralization of IFN-γ in pIgR KO mice modulated MNV titers, implicating the antiviral cytokine in the phenotype. Reduced gastrointestinal infection in pIgR KO mice was also observed with another enteric virus, reovirus. Collectively, our findings suggest that natural sIg are not protective during enteric virus infection, but rather, that sIg promote enteric viral infection through alterations in microbial immune responses.IMPORTANCE Enteric virus, such as norovirus, infections cause significant morbidity and mortality worldwide. However, direct antiviral infection prevention strategies are limited. Blocking host entry and initiation of infection provides an established avenue for intervention. Here, we investigated the role of the polymeric immunoglobulin receptor (pIgR)-secretory immunoglobulin (sIg) cycle during enteric virus infections. The innate immune functions of sIg (agglutination, immune exclusion, neutralization, and expulsion) were not required during control of acute murine norovirus (MNV) infection. Instead, lack of pIgR resulted in increased IFN-γ levels, which contributed to reduced MNV titers. Another enteric virus, reovirus, also showed decreased infection in pIgR KO mice. Collectively, our data point to a model in which sIg-mediated microbial sensing promotes norovirus and reovirus infection. These data provide the first evidence of the proviral role of natural sIg during enteric virus infections and provide another example of how intestinal bacterial communities indirectly influence MNV pathogenesis.
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Pan X, Ke H, Niu X, Li S, Lv J, Pan L. Protection Against Helicobacter pylori Infection in BALB/c Mouse Model by Oral Administration of Multivalent Epitope-Based Vaccine of Cholera Toxin B Subunit-HUUC. Front Immunol 2018; 9:1003. [PMID: 29867978 PMCID: PMC5951970 DOI: 10.3389/fimmu.2018.01003] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 04/23/2018] [Indexed: 12/20/2022] Open
Abstract
Vaccination is an increasingly important alternative approach to control Helicobacter pylori infection, since H. pylori resistance to previously efficacious antibiotic regimens is increased, and H. pylori eradication treatment for upper gastrointestinal diseases is becoming less successful. Fortunately, an efficient oral monovalent H. pylori vaccine has been developed. However, compared with monovalent vaccines, multivalent vaccines have the potential to induce more effective and comprehensive protection against H. pylori infection. In this study, we designed and produced a multivalent epitope-based vaccine cholera toxin B subunit (CTB)-HUUC with the intramucosal adjuvant CTB and tandem copies of B-cell epitopes (HpaA132-141, UreA183-203, and UreB321-339) and T-cell epitopes (HpaA88-100, UreA27-53, UreB229-251, UreB317-329, UreB373-385, UreB438-452, UreB546-561, CagA149-164, and CagA196-217) from H. pylori adhesion A subunit (HpaA), urease A subunit (UreA), urease B subunit (UreB), and cytotoxin-associated antigen (CagA). Serum IgG, stomach, and intestine mucosal sIgA from mice after CTB-HUUC vaccination neutralized H. pylori urease activity in vitro. CTB-HUUC vaccination promoted H. pylori-specific lymphocyte responses and a mixed CD4+ T cell immune response as indicated by IFN-γ, interleukin-4, and interleukin-17 production in mice. Both oral prophylactic and therapeutic CTB-HUUC vaccinations reduced gastric urease activity and H. pylori infection and protected stomachs in mice. Taken together, CTB-HUUC is a promising potent and safe multivalent vaccine in controlling H. pylori infection in BALB/c mouse model.
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Affiliation(s)
- Xing Pan
- Institute of Infection and Immunity, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Hong Ke
- Department of Hemotology, People's Hospital, Hubei University of Medicine, Shiyan, China
| | - Xiaojuan Niu
- Department of Pharmacology, Hubei University of Medicine, Shiyan, China
| | - Shan Li
- Institute of Infection and Immunity, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Jun Lv
- Institute of Infection and Immunity, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Longrui Pan
- Department of Pharmacology, Hubei University of Medicine, Shiyan, China
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Turula H, Wobus CE. The Role of the Polymeric Immunoglobulin Receptor and Secretory Immunoglobulins during Mucosal Infection and Immunity. Viruses 2018; 10:E237. [PMID: 29751532 PMCID: PMC5977230 DOI: 10.3390/v10050237] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 04/27/2018] [Accepted: 04/30/2018] [Indexed: 12/25/2022] Open
Abstract
The gastrointestinal tract houses millions of microbes, and thus has evolved several host defense mechanisms to keep them at bay, and prevent their entry into the host. One such mucosal surface defense is the secretion of secretory immunoglobulins (SIg). Secretion of SIg depends on the polymeric immunoglobulin receptor (pIgR), which transports polymeric Ig (IgA or IgM) from the basolateral surface of the epithelium to the apical side. Upon reaching the luminal side, a portion of pIgR, called secretory component (SC) is cleaved off to release Ig, forming SIg. Through antigen-specific and non-specific binding, SIg can modulate microbial communities and pathogenic microbes via several mechanisms: agglutination and exclusion from the epithelial surface, neutralization, or via host immunity and complement activation. Given the crucial role of SIg as a microbial scavenger, some pathogens also evolved ways to modulate and utilize pIgR and SIg to facilitate infection. This review will cover the regulation of the pIgR/SIg cycle, mechanisms of SIg-mediated mucosal protection as well as pathogen utilization of SIg.
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Affiliation(s)
- Holly Turula
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
- Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Christiane E Wobus
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
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15
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Bioley G, Monnerat J, Lötscher M, Vonarburg C, Zuercher A, Corthésy B. Plasma-Derived Polyreactive Secretory-Like IgA and IgM Opsonizing Salmonella enterica Typhimurium Reduces Invasion and Gut Tissue Inflammation through Agglutination. Front Immunol 2017; 8:1043. [PMID: 28900429 PMCID: PMC5581814 DOI: 10.3389/fimmu.2017.01043] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 08/11/2017] [Indexed: 12/27/2022] Open
Abstract
Due to the increasing emergence of antibiotic-resistant strains of enteropathogenic bacteria, development of alternative treatments to fight against gut infections is a major health issue. While vaccination requires that a proper combination of antigen, adjuvant, and delivery route is defined to elicit protective immunity at mucosae, oral delivery of directly active antibody preparations, referred to as passive immunization, sounds like a valuable alternative. Along the gut, the strategy suffers, however, from the difficulty to obtain sufficient amounts of antibodies with the appropriate specificity and molecular structure for mucosal delivery. Physiologically, at the antibody level, the protection of gastrointestinal mucosal surfaces against enteropathogens is principally mediated by secretory IgA and secretory IgM. We previously demonstrated that purified human plasma-derived IgA and IgM can be associated with secretory component to generate biologically active secretory-like IgA and IgM (SCIgA/M) that can protect epithelial cells from infection by Shigella flexneri in vitro. In this study, we aimed at evaluating the protective potential of these antibody preparations in vivo. We now establish that such polyreactive preparations bind efficiently to Salmonella enterica Typhimurium and trigger bacterial agglutination, as observed by laser scanning confocal microscopy. Upon delivery into a mouse ligated intestinal loop, SCIgA/M-mediated aggregates persist in the intestinal environment and limit the entry of bacteria into intestinal Peyer’s patches via immune exclusion. Moreover, oral administration to mice of immune complexes composed of S. Typhimurium and SCIgA/M reduces mucosal infection, systemic dissemination, and local inflammation. Altogether, our data provide valuable clues for the future appraisal of passive oral administration of polyreactive plasma-derived SCIgA/M to combat infection by a variety of enteropathogens.
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Affiliation(s)
- Gilles Bioley
- R&D Laboratory, Division of Immunology and Allergy, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Justine Monnerat
- R&D Laboratory, Division of Immunology and Allergy, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | | | | | | | - Blaise Corthésy
- R&D Laboratory, Division of Immunology and Allergy, Lausanne University Hospital (CHUV), Lausanne, Switzerland
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16
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Nezafat N, Eslami M, Negahdaripour M, Rahbar MR, Ghasemi Y. Designing an efficient multi-epitope oral vaccine against Helicobacter pylori using immunoinformatics and structural vaccinology approaches. MOLECULAR BIOSYSTEMS 2017; 13:699-713. [PMID: 28194462 DOI: 10.1039/c6mb00772d] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Helicobacter pylori is the cunning bacterium that can live in the stomachs of many people without any symptoms, but gradually can lead to gastric cancer. Due to various obstacles, which are related to anti-H. pylori antibiotic therapy, recently developing an anti-H. pylori vaccine has attracted more attention. In this study, different immunoinformatics and computational vaccinology approaches were employed to design an efficient multi-epitope oral vaccine against H. pylori. Our multi-epitope vaccine is composed of heat labile enterotoxin IIc B (LT-IIc) that is used as a mucosal adjuvant to enhance vaccine immunogenicity for oral immunization, cartilage oligomeric matrix protein (COMP) to increase vaccine stability in acidic pH of gut, one experimentally protective antigen, OipA, and two hypothetical protective antigens, HP0487 and HP0906, and "CTGKSC" peptide motif that target epithelial microfold cells (M cells) to enhance vaccine uptake from the gut barrier. All the aforesaid segments were joined to each other by proper linkers. The vaccine construct was modeled, validated, and refined by different programs to achieve a high-quality 3D structure. The resulting high-quality model was applied for conformational B-cell epitopes selection and docking analyses with a toll-like receptor 2 (TLR2). Moreover, molecular dynamics studies demonstrated that the protein-TLR2 docked model was stable during simulation time. We believe that our vaccine candidate can induce mucosal sIgA and IgG antibodies, and Th1/Th2/Th17-mediated protective immunity that are crucial for eradicating H. pylori infection. In sum, the computational results suggest that our newly designed vaccine could serve as a promising anti-H. pylori vaccine candidate.
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Affiliation(s)
- Navid Nezafat
- Pharmaceutical Science Research Center, Shiraz University of Medical Science, Shiraz, Iran
| | - Mahboobeh Eslami
- Pharmaceutical Science Research Center, Shiraz University of Medical Science, Shiraz, Iran
| | - Manica Negahdaripour
- Pharmaceutical Science Research Center, Shiraz University of Medical Science, Shiraz, Iran and Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mohammad Reza Rahbar
- Pharmaceutical Science Research Center, Shiraz University of Medical Science, Shiraz, Iran and Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Younes Ghasemi
- Pharmaceutical Science Research Center, Shiraz University of Medical Science, Shiraz, Iran and Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. and Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
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17
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Armitage CW, O'Meara CP, Beagley KW. Chlamydial infection enhances expression of the polymeric immunoglobulin receptor (pIgR) and transcytosis of IgA. Am J Reprod Immunol 2016; 77. [PMID: 27868280 DOI: 10.1111/aji.12611] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 11/03/2016] [Indexed: 11/27/2022] Open
Abstract
PROBLEM The pIgR mediates transport of IgA into the lumen of mucosal tissues preventing pathogenic infection. Despite this, the expression of pIgR during chlamydial infections of the male and female reproductive tracts remains poorly understood. METHOD OF STUDY The expression of pIgR in response to hormone cycling or over the course of chlamydial infection was determined in vitro and in vivo by Western blot or immunohistochemistry. RESULTS PIgR was upregulated in response to Chlamydia spp. infection of human epithelia, in both male and female mouse reproductive tracts. PIgR expression was found to be highest during estrus in the cervicovaginal and uterine epithelia and lowest during diestrus or following hormonal synchronization with Depo-Provera. Chlamydial infection of mice mediates upregulation of pIgR and transcytosis of IgA into the lumen. CONCLUSIONS Our results suggest that chlamydial infection enhances IgA secretion and pIgR expression by epithelia in the lower reproductive tracts of females and males, and hormone synchronization downregulates pIgR expression and transcytosis of IgA prior to challenge.
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Affiliation(s)
- Charles W Armitage
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Qld, Australia
| | - Connor P O'Meara
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Qld, Australia.,Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Baden-Wurttemberg, Germany
| | - Kenneth W Beagley
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Qld, Australia
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18
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Wang Y, Yang GB. Alteration of Polymeric Immunoglobulin Receptor and Neonatal Fc Receptor Expression in the Gut Mucosa of Immunodeficiency Virus-Infected Rhesus Macaques. Scand J Immunol 2016; 83:235-43. [PMID: 26860548 DOI: 10.1111/sji.12416] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 01/27/2016] [Indexed: 12/15/2022]
Abstract
Polymeric immunoglobulin receptors (pIgR) and neonatal Fc receptors (FcRn) are crucial immunoglobulin (Ig) receptors for the transcytosis of immunoglobulins, that is IgA, IgM and IgG, the levels of which in mucosal secretions were altered in both HIV- and SIV-infected individuals. To gain an insight into the changes of pIgR and FcRn expression after immunodeficiency virus (SHIV/SIV) infection, real-time RT-PCR methods were established and the mRNA levels of pIgR and FcRn in normal and SHIV/SIV-infected rhesus macaques were quantitatively examined. It was found that the levels of pIgR mRNA were within a range of 10(7) copies per million copies of GAPDH mRNA in the gut mucosa of rhesus macaques, which were up to 55 times higher than that in the oral mucosa, the highest among the non-gut tissues examined. Levels of FcRn mRNA were generally lower than that of pIgR, and the levels of FcRn mRNA in the gut mucosa were also lower than that in most non-gut tissues examined. Notably, the levels of pIgR mRNA in the duodenal mucosa were positively correlated with that of IL-17A in normal rhesus macaques. Both pIgR and FcRn mRNA levels were significantly reduced in the duodenal mucosa during acute SHIV infection and in the jejunum and caecum during chronic SHIV/SIV infection. These data expanded our knowledge on the expression of pIgR and FcRn in the gastrointestinal tract of rhesus macaques and demonstrated altered expression of pIgR and FcRn in SHIV/SIV, and by extension HIV infections, which might have contributed to HIV/AIDS pathogenesis.
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Affiliation(s)
- Y Wang
- National Center for AIDS/STD Control and Prevention, Beijing, China.,Dalian Center for Disease Control and Prevention, Dalian, China
| | - G B Yang
- National Center for AIDS/STD Control and Prevention, Beijing, China
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19
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Yang J, Dai LX, Pan X, Wang H, Li B, Zhu J, Li MY, Shi XL, Wang BN. Protection against Helicobacter pylori infection in BALB/c mice by oral administration of multi-epitope vaccine of CTB-UreI-UreB. Pathog Dis 2015; 73:ftv026. [PMID: 25846576 DOI: 10.1093/femspd/ftv026] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2015] [Indexed: 12/26/2022] Open
Abstract
Chronic gastric infection by the Gram-negative bacterium Helicobacter pylori (H. pylori) is strongly associated with gastritis, gastric ulcer and the development of distal gastric carcinoma and gastric mucosal lymphoma in humans. Antibiotic treatment of H. pylori is becoming less effective because of increasing antibiotic resistance; other treatment approaches such as specifically targeted methods, etc. to destroy this organism would be beneficial. An epitope vaccine is a promising option for protection against H. pylori infection. In this study, a multi-epitope vaccine was constructed by linking cholera toxin B subunit (CTB), two antigenic fragments of H. pylori urease I subunit (UreI20-29, UreI98-107) and four antigenic fragments of H. pylori urease B subunit (UreB12-23, UreB229-251, UreB327-400, UreB515-561), resulting in the recombinant CTB-UreI-UreB (BIB). Its protective effect against H. pylori infection was evaluated in BALB/c mice. Significant protection against H. pylori challenge was achieved in BALB/c mice immunized with BIB (15/18, 83.3%), rIB plus rCTB (6/18, 33.3%) and rIB (2/18, 11.1%) separately, while no protective effect was found in the mice immunized with either adjuvant rCTB alone or PBS. The induction of significant protection against H. pylori is possibly mediated by specific serum IgA and mucosal sIgA antibodies, and a mixed Th1/Th2/Th17 cells response. This multi-epitope vaccine might be a promising vaccine candidate that helps to control H. pylori infection.
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Affiliation(s)
- Jing Yang
- Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China Sichuan Vaccine Technology Co. Ltd, Chengdu, Sichuan 610041, People's Republic of China Department of Infectious Disease, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, People's Republic of China Department of Microbiology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Lv-xia Dai
- Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China Experiment Teaching Center of Clinical Medicine, Chengdu College of Medicine, Chengdu, Sichuan 610500, People's Republic of China
| | - Xing Pan
- Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China Sichuan Vaccine Technology Co. Ltd, Chengdu, Sichuan 610041, People's Republic of China
| | - Hongren Wang
- Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Bei Li
- Department of Infectious Disease, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, People's Republic of China Department of Microbiology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Jie Zhu
- Sichuan Vaccine Technology Co. Ltd, Chengdu, Sichuan 610041, People's Republic of China
| | - Ming-yuan Li
- Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Xin-Li Shi
- Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, People's Republic of China
| | - Bao-ning Wang
- Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
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20
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Simpfendorfer KR, Strugnell RA, Brodnicki TC, Wijburg OLC. Increased autoimmune diabetes in pIgR-deficient NOD mice is due to a "Hitchhiking" interval that refines the genetic effect of Idd5.4. PLoS One 2015; 10:e0121979. [PMID: 25835383 PMCID: PMC4383422 DOI: 10.1371/journal.pone.0121979] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 02/05/2015] [Indexed: 01/12/2023] Open
Abstract
Selective breeding to introduce a gene mutation from one mouse strain onto the genetic background of another strain invariably produces “hitchhiking” (i.e. flanking) genomic intervals, which may independently affect a disease trait of interest. To investigate a role for the polymeric Ig receptor in autoimmune diabetes, a congenic nonobese diabetic (NOD) mouse strain was generated that harbors a Pigr null allele derived from C57BL/6 (B6) mice. These pIgR-deficient NOD mice exhibited increased serum IgA along with an increased diabetes incidence. However, the Pigr null allele was encompassed by a relatively large “hitchhiking” genomic interval that was derived from B6 mice and overlaps Idd5.4, a susceptibility locus for autoimmune diabetes. Additional congenic NOD mouse strains, harboring smaller B6-derived intervals, confirmed Idd5.4 independently of the other three known susceptibility loci on chromosome 1, and further localized Idd5.4 to an interval proximal to Pigr. Moreover, these congenic NOD mice showed that B6 mice harbor a more diabetogenic allele than NOD mice for this locus. The smallest B6-derived interval encompassing the Pigr null allele may, however, confer a small degree of protection against diabetes, but this protection appears to be dependent on the absence of the diabetogenic B6 allele for Idd5.4. This study provides another example of the potential hidden effects of “hitchhiking" genomic intervals and how such intervals can be used to localize disease susceptibility loci.
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MESH Headings
- Age Factors
- Alleles
- Animals
- Chromosome Mapping
- Chromosomes, Mammalian/chemistry
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/pathology
- Disease Models, Animal
- Female
- Genetic Loci
- Genetic Predisposition to Disease
- Genome
- Humans
- Immunoglobulin A/blood
- Immunoglobulin A/genetics
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, Transgenic
- Receptors, Polymeric Immunoglobulin/deficiency
- Receptors, Polymeric Immunoglobulin/genetics
- Receptors, Polymeric Immunoglobulin/immunology
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Affiliation(s)
- Kim R. Simpfendorfer
- The Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia
| | - Richard A. Strugnell
- The Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia
- The Australian Bacterial Pathogenesis Program, The University of Melbourne, Parkville, Victoria, Australia
| | - Thomas C. Brodnicki
- Immunology & Diabetes Unit, St Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
| | - Odilia L. C. Wijburg
- The Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia
- The Australian Bacterial Pathogenesis Program, The University of Melbourne, Parkville, Victoria, Australia
- * E-mail:
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22
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Abstract
Peptic ulcer bleeding and recurrence rate are strongly linked to Helicobacter pylori infection even if nonsteroidal anti-inflammatory drugs (NSAIDs) play a relevant role in this setting. Further studies confirm that H. pylori eradication lowers the risk of recurrent peptic ulcer bleeding. Therefore, a test-and-treat strategy appears to be mandatory for patients with a history of ulcer bleeding and NSAIDs and/or aspirin use. Concerning gastroesophageal reflux disease (GERD), evidence clearly shows that H. pylori status has no effect on symptoms and treatment. Therefore, H. pylori treatment is not contraindicated in patients with GERD. The exact role of H. pylori in functional dyspepsia (FD) remains controversial. Novel possible mechanisms by which H. pylori may elicit dyspeptic symptoms include alterations of gastric motility, as well as endocrine and acid-secretory abnormalities. Hunger sensations, acid secretion, and gastrointestinal motility are regulated by ghrelin, particularly produced by the gastric enteroendocrine cell compartment. The improvement of symptoms correlates with enhanced plasma ghrelin levels. Apart from the need for more trials on this topic, these findings may give insight into the underlying pathophysiology of FD symptoms. Recent reports suggest that the presence of bacterial DNA in the oral cavity may be relevant to its transmission. A potential protective role of H. pylori on inflammatory bowel diseases needs to be better elucidated.
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Affiliation(s)
- Enzo Ierardi
- Department of Emergency and Organ Transplantation, University of Bari - AOU Policlinico, Piazza Giulio Cesare 10, 70124, Bari, Italy
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23
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Moyat M, Velin D. Immune responses to Helicobacter pylori infection. World J Gastroenterol 2014; 20:5583-5593. [PMID: 24914318 PMCID: PMC4024767 DOI: 10.3748/wjg.v20.i19.5583] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 12/13/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is one of the most common infections in human beings worldwide. H. pylori express lipopolysaccharides and flagellin that do not activate efficiently Toll-like receptors and express dedicated effectors, such as γ-glutamyl transpeptidase, vacuolating cytotoxin (vacA), arginase, that actively induce tolerogenic signals. In this perspective, H. pylori can be considered as a commensal bacteria belonging to the stomach microbiota. However, when present in the stomach, H. pylori reduce the overall diversity of the gastric microbiota and promote gastric inflammation by inducing Nod1-dependent pro-inflammatory program and by activating neutrophils through the production of a neutrophil activating protein. The maintenance of a chronic inflammation in the gastric mucosa and the direct action of virulence factors (vacA and cytotoxin-associated gene A) confer pro-carcinogenic activities to H. pylori. Hence, H. pylori cannot be considered as symbiotic bacteria but rather as part of the pathobiont. The development of a H. pylori vaccine will bring health benefits for individuals infected with antibiotic resistant H. pylori strains and population of underdeveloped countries.
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