<italic toggle="yes">Entamoeba histolytica</italic>-Induced Mucin Exocytosis Is Mediated by VAMP8 and Is Critical in Mucosal Innate Host Defense
ABSTRACT Intestinal mucus secretion is critical in maintaining mucosal host defense against a myriad of pathogens by preventing direct association with the epithelium. Entamoeba histolytica specifically binds colonic MUC2 mucin and also induces potent hypersecretion from goblet cells; however, chara...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2017-11-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01323-17 |
| _version_ | 1819010224311238656 |
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| author | Steve Cornick France Moreau Herbert Y. Gaisano Kris Chadee |
| author_facet | Steve Cornick France Moreau Herbert Y. Gaisano Kris Chadee |
| author_sort | Steve Cornick |
| collection | DOAJ |
| description | ABSTRACT Intestinal mucus secretion is critical in maintaining mucosal host defense against a myriad of pathogens by preventing direct association with the epithelium. Entamoeba histolytica specifically binds colonic MUC2 mucin and also induces potent hypersecretion from goblet cells; however, characterization of the nature of the mechanisms controlling mucus release remains elusive. In this report, we identify vesicle SNARE vesicle-associated membrane protein 8 (VAMP8) present on mucin granules as orchestrating regulated exocytosis in human goblet cells in response to the presence of E. histolytica. VAMP8 was specifically activated during E. histolytica infection, and ablation of VAMP8 led to impaired mucin secretion. As a consequence, loss of VAMP8 increased E. histolytica adherence to epithelial cells associated with enhanced cell death through apoptosis characterized by caspase 3 and 9 cleavages and DNA fragmentation. With the mucosal barrier compromised in Vamp8−/− animals, E. histolytica induced an aggressive proinflammatory response with elevated levels of interleukin-1 alpha (IL-1α), IL-1β, and tumor necrosis factor alpha (TNF-α) secretion. This report is the first to characterize regulated mucin exocytosis in intestinal goblet cells in response to a pathogen and the downstream consequences of improper mucin secretion in mucosal barrier defense. IMPORTANCE The intestinal tract is exposed to countless substances and pathogens, and yet homeostasis is maintained, in part by the mucus layer that houses the microbiota and spatially separates potential threats from the underlying single layer of epithelium. Despite the critical role of mucus in innate host defense, characterization of the mechanisms by which mucus is secreted from specialized goblet cells in the gut remains elusive. Here, we describe the machinery that regulates mucus secretion as well as the consequence during infection with the colonic pathogen Entamoeba histolytica. Abolishment of the key machinery protein VAMP8 abrogated mucus release in cultured human colonic goblet cells and during E. histolytica infection in Vamp8−/− mice, which showed enhanced amoeba contact and killing of epithelial cells, triggering a potent proinflammatory response. This report highlights the importance of the VAMP8 secretory machinery in facilitating mucus release from intestinal goblet cells and the dire consequences that occur during disease pathogenesis if these pathways are not functional. |
| first_indexed | 2024-12-21T01:08:52Z |
| format | Article |
| id | doaj.art-6277f5652417403386d6c343a436d86e |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-21T01:08:52Z |
| publishDate | 2017-11-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-6277f5652417403386d6c343a436d86e2022-12-21T19:20:59ZengAmerican Society for MicrobiologymBio2150-75112017-11-018510.1128/mBio.01323-17<italic toggle="yes">Entamoeba histolytica</italic>-Induced Mucin Exocytosis Is Mediated by VAMP8 and Is Critical in Mucosal Innate Host DefenseSteve Cornick0France Moreau1Herbert Y. Gaisano2Kris Chadee3Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, CanadaDepartment of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, CanadaDepartments of Medicine and Physiology, University of Toronto, Toronto, Ontario, CanadaDepartment of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, CanadaABSTRACT Intestinal mucus secretion is critical in maintaining mucosal host defense against a myriad of pathogens by preventing direct association with the epithelium. Entamoeba histolytica specifically binds colonic MUC2 mucin and also induces potent hypersecretion from goblet cells; however, characterization of the nature of the mechanisms controlling mucus release remains elusive. In this report, we identify vesicle SNARE vesicle-associated membrane protein 8 (VAMP8) present on mucin granules as orchestrating regulated exocytosis in human goblet cells in response to the presence of E. histolytica. VAMP8 was specifically activated during E. histolytica infection, and ablation of VAMP8 led to impaired mucin secretion. As a consequence, loss of VAMP8 increased E. histolytica adherence to epithelial cells associated with enhanced cell death through apoptosis characterized by caspase 3 and 9 cleavages and DNA fragmentation. With the mucosal barrier compromised in Vamp8−/− animals, E. histolytica induced an aggressive proinflammatory response with elevated levels of interleukin-1 alpha (IL-1α), IL-1β, and tumor necrosis factor alpha (TNF-α) secretion. This report is the first to characterize regulated mucin exocytosis in intestinal goblet cells in response to a pathogen and the downstream consequences of improper mucin secretion in mucosal barrier defense. IMPORTANCE The intestinal tract is exposed to countless substances and pathogens, and yet homeostasis is maintained, in part by the mucus layer that houses the microbiota and spatially separates potential threats from the underlying single layer of epithelium. Despite the critical role of mucus in innate host defense, characterization of the mechanisms by which mucus is secreted from specialized goblet cells in the gut remains elusive. Here, we describe the machinery that regulates mucus secretion as well as the consequence during infection with the colonic pathogen Entamoeba histolytica. Abolishment of the key machinery protein VAMP8 abrogated mucus release in cultured human colonic goblet cells and during E. histolytica infection in Vamp8−/− mice, which showed enhanced amoeba contact and killing of epithelial cells, triggering a potent proinflammatory response. This report highlights the importance of the VAMP8 secretory machinery in facilitating mucus release from intestinal goblet cells and the dire consequences that occur during disease pathogenesis if these pathways are not functional.https://journals.asm.org/doi/10.1128/mBio.01323-17Entamoeba histolyticaexocytosisgoblet cellsgut inflammationinnate immunitymucin |
| spellingShingle | Steve Cornick France Moreau Herbert Y. Gaisano Kris Chadee <italic toggle="yes">Entamoeba histolytica</italic>-Induced Mucin Exocytosis Is Mediated by VAMP8 and Is Critical in Mucosal Innate Host Defense mBio Entamoeba histolytica exocytosis goblet cells gut inflammation innate immunity mucin |
| title | <italic toggle="yes">Entamoeba histolytica</italic>-Induced Mucin Exocytosis Is Mediated by VAMP8 and Is Critical in Mucosal Innate Host Defense |
| title_full | <italic toggle="yes">Entamoeba histolytica</italic>-Induced Mucin Exocytosis Is Mediated by VAMP8 and Is Critical in Mucosal Innate Host Defense |
| title_fullStr | <italic toggle="yes">Entamoeba histolytica</italic>-Induced Mucin Exocytosis Is Mediated by VAMP8 and Is Critical in Mucosal Innate Host Defense |
| title_full_unstemmed | <italic toggle="yes">Entamoeba histolytica</italic>-Induced Mucin Exocytosis Is Mediated by VAMP8 and Is Critical in Mucosal Innate Host Defense |
| title_short | <italic toggle="yes">Entamoeba histolytica</italic>-Induced Mucin Exocytosis Is Mediated by VAMP8 and Is Critical in Mucosal Innate Host Defense |
| title_sort | italic toggle yes entamoeba histolytica italic induced mucin exocytosis is mediated by vamp8 and is critical in mucosal innate host defense |
| topic | Entamoeba histolytica exocytosis goblet cells gut inflammation innate immunity mucin |
| url | https://journals.asm.org/doi/10.1128/mBio.01323-17 |
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