The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis
Destruction of the pulmonary epithelium is a major feature of lung diseases caused by the mould pathogen Aspergillus fumigatus. Although it is widely postulated that tissue invasion is governed by fungal proteases, A. fumigatus mutants lacking individual or multiple enzymes remain fully invasive, su...
| Autores: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2014 |
| País: | España |
| Institución: | Instituto de Salud Carlos III (ISCIII) |
| Repositorio: | Repisalud |
| Idioma: | inglés |
| OAI Identifier: | oai:repisalud.isciii.es:20.500.12105/6837 |
| Acceso en línea: | http://hdl.handle.net/20.500.12105/6837 |
| Access Level: | acceso abierto |
| Palabra clave: | Animals Aspergillus fumigatus Epithelial Cells Fungal Proteins Hydrogen-Ion Concentration Mice Pulmonary Aspergillosis Transcription Factors |
| id |
ES_77c77ddf4cf21e5aa5d9bdafdcfb800c |
|---|---|
| oai_identifier_str |
oai:repisalud.isciii.es:20.500.12105/6837 |
| network_acronym_str |
ES |
| network_name_str |
España |
| repository_id_str |
|
| spelling |
The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosisBertuzzi, MargheritaSchrettl, MarkusAlcazar-Fuoli, LauraCairns, Timothy CMuñoz, AlbertoWalker, Louise AHerbst, SusanneSafari, MaryamCheverton, Angela MChen, DanLiu, HongSaijo, ShinobuFedorova, Natalie DArmstrong-James, DariusMunro, Carol ARead, Nick DFiller, Scott GEspeso, Eduardo ANierman, William CHaas, HubertusBignell, Elaine MAnimalsAspergillus fumigatusEpithelial CellsFungal ProteinsHydrogen-Ion ConcentrationMicePulmonary AspergillosisTranscription FactorsDestruction of the pulmonary epithelium is a major feature of lung diseases caused by the mould pathogen Aspergillus fumigatus. Although it is widely postulated that tissue invasion is governed by fungal proteases, A. fumigatus mutants lacking individual or multiple enzymes remain fully invasive, suggesting a concomitant requirement for other pathogenic activities during host invasion. In this study we discovered, and exploited, a novel, tissue non-invasive, phenotype in A. fumigatus mutants lacking the pH-responsive transcription factor PacC. Our study revealed a novel mode of epithelial entry, occurring in a cell wall-dependent manner prior to protease production, and via the Dectin-1 β-glucan receptor. ΔpacC mutants are defective in both contact-mediated epithelial entry and protease expression, and significantly attenuated for pathogenicity in leukopenic mice. We combined murine infection modelling, in vivo transcriptomics, and in vitro infections of human alveolar epithelia, to delineate two major, and sequentially acting, PacC-dependent processes impacting epithelial integrity in vitro and tissue invasion in the whole animal. We demonstrate that A. fumigatus spores and germlings are internalised by epithelial cells in a contact-, actin-, cell wall- and Dectin-1 dependent manner and ΔpacC mutants, which aberrantly remodel the cell wall during germinative growth, are unable to gain entry into epithelial cells, both in vitro and in vivo. We further show that PacC acts as a global transcriptional regulator of secreted molecules during growth in the leukopenic mammalian lung, and profile the full cohort of secreted gene products expressed during invasive infection. Our study reveals a combinatorial mode of tissue entry dependent upon sequential, and mechanistically distinct, perturbations of the pulmonary epithelium and demonstrates, for the first time a protective role for Dectin-1 blockade in epithelial defences. Infecting ΔpacC mutants are hypersensitive to cell wall-active antifungal agents highlighting the value of PacC signalling as a target for antifungal therapy.Public Library of Science (PLOS)Medical Research Council (Reino Unido)Biotechnology and Biological Sciences Research Council (Reino Unido)Wellcome TrustImperial College London (Reino Unido)FWF Austrian Science FundNational Institutes of Health (Estados Unidos)20182018-12-1320142014-10-1620142014-10-16journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/20.500.12105/6837reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/68372026-06-12T12:43:37Z |
| dc.title.none.fl_str_mv |
The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis |
| title |
The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis |
| spellingShingle |
The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis Bertuzzi, Margherita Animals Aspergillus fumigatus Epithelial Cells Fungal Proteins Hydrogen-Ion Concentration Mice Pulmonary Aspergillosis Transcription Factors |
| title_short |
The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis |
| title_full |
The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis |
| title_fullStr |
The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis |
| title_full_unstemmed |
The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis |
| title_sort |
The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis |
| dc.creator.none.fl_str_mv |
Bertuzzi, Margherita Schrettl, Markus Alcazar-Fuoli, Laura Cairns, Timothy C Muñoz, Alberto Walker, Louise A Herbst, Susanne Safari, Maryam Cheverton, Angela M Chen, Dan Liu, Hong Saijo, Shinobu Fedorova, Natalie D Armstrong-James, Darius Munro, Carol A Read, Nick D Filler, Scott G Espeso, Eduardo A Nierman, William C Haas, Hubertus Bignell, Elaine M |
| author |
Bertuzzi, Margherita |
| author_facet |
Bertuzzi, Margherita Schrettl, Markus Alcazar-Fuoli, Laura Cairns, Timothy C Muñoz, Alberto Walker, Louise A Herbst, Susanne Safari, Maryam Cheverton, Angela M Chen, Dan Liu, Hong Saijo, Shinobu Fedorova, Natalie D Armstrong-James, Darius Munro, Carol A Read, Nick D Filler, Scott G Espeso, Eduardo A Nierman, William C Haas, Hubertus Bignell, Elaine M |
| author_role |
author |
| author2 |
Schrettl, Markus Alcazar-Fuoli, Laura Cairns, Timothy C Muñoz, Alberto Walker, Louise A Herbst, Susanne Safari, Maryam Cheverton, Angela M Chen, Dan Liu, Hong Saijo, Shinobu Fedorova, Natalie D Armstrong-James, Darius Munro, Carol A Read, Nick D Filler, Scott G Espeso, Eduardo A Nierman, William C Haas, Hubertus Bignell, Elaine M |
| author2_role |
author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Medical Research Council (Reino Unido) Biotechnology and Biological Sciences Research Council (Reino Unido) Wellcome Trust Imperial College London (Reino Unido) FWF Austrian Science Fund National Institutes of Health (Estados Unidos) |
| dc.subject.none.fl_str_mv |
Animals Aspergillus fumigatus Epithelial Cells Fungal Proteins Hydrogen-Ion Concentration Mice Pulmonary Aspergillosis Transcription Factors |
| topic |
Animals Aspergillus fumigatus Epithelial Cells Fungal Proteins Hydrogen-Ion Concentration Mice Pulmonary Aspergillosis Transcription Factors |
| description |
Destruction of the pulmonary epithelium is a major feature of lung diseases caused by the mould pathogen Aspergillus fumigatus. Although it is widely postulated that tissue invasion is governed by fungal proteases, A. fumigatus mutants lacking individual or multiple enzymes remain fully invasive, suggesting a concomitant requirement for other pathogenic activities during host invasion. In this study we discovered, and exploited, a novel, tissue non-invasive, phenotype in A. fumigatus mutants lacking the pH-responsive transcription factor PacC. Our study revealed a novel mode of epithelial entry, occurring in a cell wall-dependent manner prior to protease production, and via the Dectin-1 β-glucan receptor. ΔpacC mutants are defective in both contact-mediated epithelial entry and protease expression, and significantly attenuated for pathogenicity in leukopenic mice. We combined murine infection modelling, in vivo transcriptomics, and in vitro infections of human alveolar epithelia, to delineate two major, and sequentially acting, PacC-dependent processes impacting epithelial integrity in vitro and tissue invasion in the whole animal. We demonstrate that A. fumigatus spores and germlings are internalised by epithelial cells in a contact-, actin-, cell wall- and Dectin-1 dependent manner and ΔpacC mutants, which aberrantly remodel the cell wall during germinative growth, are unable to gain entry into epithelial cells, both in vitro and in vivo. We further show that PacC acts as a global transcriptional regulator of secreted molecules during growth in the leukopenic mammalian lung, and profile the full cohort of secreted gene products expressed during invasive infection. Our study reveals a combinatorial mode of tissue entry dependent upon sequential, and mechanistically distinct, perturbations of the pulmonary epithelium and demonstrates, for the first time a protective role for Dectin-1 blockade in epithelial defences. Infecting ΔpacC mutants are hypersensitive to cell wall-active antifungal agents highlighting the value of PacC signalling as a target for antifungal therapy. |
| publishDate |
2014 |
| dc.date.none.fl_str_mv |
2014 2014-10-16 2014 2014-10-16 2018 2018-12-13 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/20.500.12105/6837 |
| url |
http://hdl.handle.net/20.500.12105/6837 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Public Library of Science (PLOS) |
| publisher.none.fl_str_mv |
Public Library of Science (PLOS) |
| dc.source.none.fl_str_mv |
reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII) |
| instname_str |
Instituto de Salud Carlos III (ISCIII) |
| reponame_str |
Repisalud |
| collection |
Repisalud |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869411146960732160 |
| score |
15,811543 |