CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative Defenses
Summary: Infection by rapidly growing Mycobacterium abscessus is increasingly prevalent in cystic fibrosis (CF), a genetic disease caused by a defective CF transmembrane conductance regulator (CFTR). However, the potential link between a dysfunctional CFTR and vulnerability to M. abscessus infection...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-02-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719301007 |
| _version_ | 1818242729589604352 |
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| author | Audrey Bernut Christian Dupont Nikolay V. Ogryzko Aymeric Neyret Jean-Louis Herrmann R. Andres Floto Stephen A. Renshaw Laurent Kremer |
| author_facet | Audrey Bernut Christian Dupont Nikolay V. Ogryzko Aymeric Neyret Jean-Louis Herrmann R. Andres Floto Stephen A. Renshaw Laurent Kremer |
| author_sort | Audrey Bernut |
| collection | DOAJ |
| description | Summary: Infection by rapidly growing Mycobacterium abscessus is increasingly prevalent in cystic fibrosis (CF), a genetic disease caused by a defective CF transmembrane conductance regulator (CFTR). However, the potential link between a dysfunctional CFTR and vulnerability to M. abscessus infection remains unknown. Herein, we exploit a CFTR-depleted zebrafish model, recapitulating CF immuno-pathogenesis, to study the contribution of CFTR in innate immunity against M. abscessus infection. Loss of CFTR increases susceptibility to infection through impaired NADPH oxidase-dependent restriction of intracellular growth and reduced neutrophil chemotaxis, which together compromise granuloma formation and integrity. As a consequence, extracellular multiplication of M. abscessus expands rapidly, inducing abscess formation and causing lethal infections. Because these phenotypes are not observed with other mycobacteria, our findings highlight the crucial and specific role of CFTR in the immune control of M. abscessus by mounting effective oxidative responses. : Bernut et al. investigate the mechanism by which cystic fibrosis patients are vulnerable to Mycobacterium abscessus infection. Using zebrafish, they show that dysfunction of CFTR reduces both macrophage bactericidal activity and neutrophil recruitment to the forming protective granulomas. Together, this leads to hypersusceptibility to M. abscessus infection and larval death. Keywords: cystic fibrosis, Mycobacterium abscessus, CFTR, NADPH oxidase, zebrafish, pathogenesis, innate immunity |
| first_indexed | 2024-12-12T13:49:52Z |
| format | Article |
| id | doaj.art-1de1555a66164a779c8130129c23e2bb |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-12T13:49:52Z |
| publishDate | 2019-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-1de1555a66164a779c8130129c23e2bb2022-12-22T00:22:36ZengElsevierCell Reports2211-12472019-02-0126718281840.e4CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative DefensesAudrey Bernut0Christian Dupont1Nikolay V. Ogryzko2Aymeric Neyret3Jean-Louis Herrmann4R. Andres Floto5Stephen A. Renshaw6Laurent Kremer7CNRS, UMR9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France; Bateson Centre, University of Sheffield, Sheffield, UK; Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK; Corresponding authorCNRS, UMR9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, FranceBateson Centre, University of Sheffield, Sheffield, UK; Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UKCNRS, UMR9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France2I, INSERM, UVSQ, Université Paris-Saclay, Versailles, FranceMolecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge, UKBateson Centre, University of Sheffield, Sheffield, UK; Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UKCNRS, UMR9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France; INSERM, IRIM, Montpellier, France; Corresponding authorSummary: Infection by rapidly growing Mycobacterium abscessus is increasingly prevalent in cystic fibrosis (CF), a genetic disease caused by a defective CF transmembrane conductance regulator (CFTR). However, the potential link between a dysfunctional CFTR and vulnerability to M. abscessus infection remains unknown. Herein, we exploit a CFTR-depleted zebrafish model, recapitulating CF immuno-pathogenesis, to study the contribution of CFTR in innate immunity against M. abscessus infection. Loss of CFTR increases susceptibility to infection through impaired NADPH oxidase-dependent restriction of intracellular growth and reduced neutrophil chemotaxis, which together compromise granuloma formation and integrity. As a consequence, extracellular multiplication of M. abscessus expands rapidly, inducing abscess formation and causing lethal infections. Because these phenotypes are not observed with other mycobacteria, our findings highlight the crucial and specific role of CFTR in the immune control of M. abscessus by mounting effective oxidative responses. : Bernut et al. investigate the mechanism by which cystic fibrosis patients are vulnerable to Mycobacterium abscessus infection. Using zebrafish, they show that dysfunction of CFTR reduces both macrophage bactericidal activity and neutrophil recruitment to the forming protective granulomas. Together, this leads to hypersusceptibility to M. abscessus infection and larval death. Keywords: cystic fibrosis, Mycobacterium abscessus, CFTR, NADPH oxidase, zebrafish, pathogenesis, innate immunityhttp://www.sciencedirect.com/science/article/pii/S2211124719301007 |
| spellingShingle | Audrey Bernut Christian Dupont Nikolay V. Ogryzko Aymeric Neyret Jean-Louis Herrmann R. Andres Floto Stephen A. Renshaw Laurent Kremer CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative Defenses Cell Reports |
| title | CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative Defenses |
| title_full | CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative Defenses |
| title_fullStr | CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative Defenses |
| title_full_unstemmed | CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative Defenses |
| title_short | CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative Defenses |
| title_sort | cftr protects against mycobacterium abscessus infection by fine tuning host oxidative defenses |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719301007 |
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