Electronic Resource
Human Plasminogen Exacerbates Clostridioides difficile Enteric Disease and Alters the Spore Surface.
| العنوان: | Human Plasminogen Exacerbates Clostridioides difficile Enteric Disease and Alters the Spore Surface. |
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| المؤلفون: | Whisstock J.C., Medcalf R.L., Sanderson-Smith M., Cordwell S.J., Law R.H.P., Lyras D., Awad M.M., Hutton M.L., Quek A.J., Klare W.P., Mileto S.J., Mackin K., Ly D., Oorschot V., Bosnjak M., Jenkin G., Conroy P.J., West N., Fulcher A., Costin A., Day C.J., Jennings M.P. |
| بيانات النشر: | W.B. Saunders United States 2020-11-25 |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Background & Aims: The protease plasmin is an important wound healing factor, but it is not clear how it affects gastrointestinal infection-mediated damage, such as that resulting from Clostridioides difficile. We investigated the role of plasmin in C difficile-associated disease. This bacterium produces a spore form that is required for infection, so we also investigated the effects of plasmin on spores. Method(s): C57BL/6J mice expressing the precursor to plasmin, the zymogen human plasminogen (hPLG), or infused with hPLG were infected with C difficile, and disease progression was monitored. Gut tissues were collected, and cytokine production and tissue damage were analyzed by using proteomic and cytokine arrays. Antibodies that inhibit either hPLG activation or plasmin activity were developed and structurally characterized, and their effects were tested in mice. Spores were isolated from infected patients or mice and visualized using super-resolution microscopy; the functional consequences of hPLG binding to spores were determined. Result(s): hPLG localized to the toxin-damaged gut, resulting in immune dysregulation with an increased abundance of cytokines (such as interleukin [IL] 1A, IL1B, IL3, IL10, IL12B, MCP1, MP1A, MP1B, GCSF, GMCSF, KC, TIMP-1), tissue degradation, and reduced survival. Administration of antibodies that inhibit plasminogen activation reduced disease severity in mice. C difficile spores bound specifically to hPLG and active plasmin degraded their surface, facilitating rapid germination. Conclusion(s): We found that hPLG is recruited to the damaged gut, exacerbating C difficile disease in mice. hPLG binds to C difficile spores, and, upon activation to plasmin, remodels the spore surface, facilitating rapid spore germination. Inhibitors of plasminogen activation might be developed for treatment of C difficile or other infection-mediated gastrointestinal diseases.Copyright © 2020 |
| مصطلحات الفهرس: | animal tissue, article, bacterial spore, Clostridium difficile infection, controlled study, cytokine production, disease exacerbation, disease severity, human, immune dysregulation, intestine infection, intestine injury, intestine tissue, mouse, nonhuman, plasminogen activation, priority journal, proteomics, spore germination, survival, tissue injury, cytokine/ec [Endogenous Compound], granulocyte colony stimulating factor/ec [Endogenous Compound], granulocyte macrophage colony stimulating factor/ec [Endogenous Compound], interleukin 10/ec [Endogenous Compound], interleukin 12p40/ec [Endogenous Compound], interleukin 1alpha/ec [Endogenous Compound], interleukin 1beta/ec [Endogenous Compound], interleukin 3/ec [Endogenous Compound], keratinocyte derived chemokine/ec [Endogenous Compound], monocyte chemotactic protein 1/ec [Endogenous Compound], plasmin/ec [Endogenous Compound], plasminogen, tissue inhibitor of metalloproteinase/ec [Endogenous Compound], unclassified drug, male, animal cell, animal experiment, animal model, mp1a protein/ec [Endogenous Compound], mp1b protein/ec [Endogenous Compound], Article |
| URL: | Gastroenterology LibKey Link |
| الاتاحة: | Open access content. Open access content Copyright 2020 Elsevier B.V., All rights reserved. |
| Other Numbers: | AUSHL oai:repository.monashhealth.org:1/28950 Gastroenterology. 159 (4) (pp 1431-1443.e6), 2020. Date of Publication: October 2020. 0016-5085 https://repository.monashhealth.org/monashhealthjspui/handle/1/28950 32574621 [http://www.ncbi.nlm.nih.gov/pubmed/?term=32574621] 2008339054 (Awad, Hutton, Mileto, Mackin, Bosnjak, Lyras) Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia (Quek, Oorschot, Conroy, Costin, Law, Whisstock) Australian Research Council Centre of Excellence in Advanced Molecular Imaging and Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia (Klare, Cordwell) School of Life and Environmental Sciences and Charles Perkins Centre, The University of Sydney, Sydney, Australia (Ly, Sanderson-Smith) Illawarra health and Medical Research Institute, Wollongong, Australia (Ly, Sanderson-Smith) School of Chemistry and Molecular Bioscience and Molecular Horizons, University of Wollongong, Wollongong, Australia (Oorschot, Fulcher) Monash Micro Imaging, Monash University, Clayton, Australia (Jenkin) Monash Infectious Diseases, Monash Health, Clayton, Australia (West) School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, University of Queensland, St. Lucia, Australia (Day, Jennings) Institute for Glycomics, Griffith University, Gold Coast, Australia (Medcalf) Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Monash University, Clayton, Australia (Whisstock) European Molecular Biology Laboratory Australia, Monash University, Clayton, Australia (Whisstock) South East University-Monash Joint Institute, Institute of Life Sciences, Southeast University, Nanjing, China Lyras D.; dena.lyras@monash.edu 1305123647 |
| المصدر المساهم: | MONASH HEALTH LIBRS From OAIster®, provided by the OCLC Cooperative. |
| رقم الانضمام: | edsoai.on1305123647 |
| قاعدة البيانات: | OAIster |
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