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Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology

Staphylococcus aureus necrotizing pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cell...

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Autores principales: Mairpady Shambat, Srikanth, Chen, Puran, Nguyen Hoang, Anh Thu, Bergsten, Helena, Vandenesch, Francois, Siemens, Nikolai, Lina, Gerard, Monk, Ian R., Foster, Timothy J., Arakere, Gayathri, Svensson, Mattias, Norrby-Teglund, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631791/
https://www.ncbi.nlm.nih.gov/pubmed/26398950
http://dx.doi.org/10.1242/dmm.021923
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author Mairpady Shambat, Srikanth
Chen, Puran
Nguyen Hoang, Anh Thu
Bergsten, Helena
Vandenesch, Francois
Siemens, Nikolai
Lina, Gerard
Monk, Ian R.
Foster, Timothy J.
Arakere, Gayathri
Svensson, Mattias
Norrby-Teglund, Anna
author_facet Mairpady Shambat, Srikanth
Chen, Puran
Nguyen Hoang, Anh Thu
Bergsten, Helena
Vandenesch, Francois
Siemens, Nikolai
Lina, Gerard
Monk, Ian R.
Foster, Timothy J.
Arakere, Gayathri
Svensson, Mattias
Norrby-Teglund, Anna
author_sort Mairpady Shambat, Srikanth
collection PubMed
description Staphylococcus aureus necrotizing pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific staphylococcal exotoxins in tissue pathology associated with severe pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing pneumonia or lung empyema, or to purified toxins. The necrotizing pneumonia strains secreted high levels of α-toxin and Panton-Valentine leukocidin (PVL), and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin from the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of α-toxin, and triggered limited tissue damage. α-toxin had a direct damaging effect on the epithelium, as verified using toxin-deficient mutants and pure α-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils. A combination of α-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with staphylococcal pneumonia revealed that strains producing high levels of α-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against α-toxin and PVL. This study introduces a novel model system for study of staphylococcal pneumonia in a human setting. The results reveal that the combination and levels of α-toxin and PVL correlate with tissue pathology and clinical outcome associated with pneumonia.
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spelling pubmed-46317912015-11-09 Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology Mairpady Shambat, Srikanth Chen, Puran Nguyen Hoang, Anh Thu Bergsten, Helena Vandenesch, Francois Siemens, Nikolai Lina, Gerard Monk, Ian R. Foster, Timothy J. Arakere, Gayathri Svensson, Mattias Norrby-Teglund, Anna Dis Model Mech Research Article Staphylococcus aureus necrotizing pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific staphylococcal exotoxins in tissue pathology associated with severe pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing pneumonia or lung empyema, or to purified toxins. The necrotizing pneumonia strains secreted high levels of α-toxin and Panton-Valentine leukocidin (PVL), and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin from the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of α-toxin, and triggered limited tissue damage. α-toxin had a direct damaging effect on the epithelium, as verified using toxin-deficient mutants and pure α-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils. A combination of α-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with staphylococcal pneumonia revealed that strains producing high levels of α-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against α-toxin and PVL. This study introduces a novel model system for study of staphylococcal pneumonia in a human setting. The results reveal that the combination and levels of α-toxin and PVL correlate with tissue pathology and clinical outcome associated with pneumonia. The Company of Biologists 2015-11-01 /pmc/articles/PMC4631791/ /pubmed/26398950 http://dx.doi.org/10.1242/dmm.021923 Text en © 2015. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Mairpady Shambat, Srikanth
Chen, Puran
Nguyen Hoang, Anh Thu
Bergsten, Helena
Vandenesch, Francois
Siemens, Nikolai
Lina, Gerard
Monk, Ian R.
Foster, Timothy J.
Arakere, Gayathri
Svensson, Mattias
Norrby-Teglund, Anna
Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology
title Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology
title_full Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology
title_fullStr Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology
title_full_unstemmed Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology
title_short Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology
title_sort modelling staphylococcal pneumonia in a human 3d lung tissue model system delineates toxin-mediated pathology
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631791/
https://www.ncbi.nlm.nih.gov/pubmed/26398950
http://dx.doi.org/10.1242/dmm.021923
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