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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-10-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004413&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849726796947259392 |
|---|---|
| author | Margherita Bertuzzi Markus Schrettl Laura Alcazar-Fuoli Timothy C Cairns Alberto Muñoz Louise A Walker Susanne Herbst Maryam Safari Angela M Cheverton Dan Chen Hong Liu Shinobu Saijo Natalie D Fedorova Darius Armstrong-James Carol A Munro Nick D Read Scott G Filler Eduardo A Espeso William C Nierman Hubertus Haas Elaine M Bignell |
| author_facet | Margherita Bertuzzi Markus Schrettl Laura Alcazar-Fuoli Timothy C Cairns Alberto Muñoz Louise A Walker Susanne Herbst Maryam Safari Angela M Cheverton Dan Chen Hong Liu Shinobu Saijo Natalie D Fedorova Darius Armstrong-James Carol A Munro Nick D Read Scott G Filler Eduardo A Espeso William C Nierman Hubertus Haas Elaine M Bignell |
| author_sort | Margherita Bertuzzi |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-eb8eb45ee83a4e99a63533f7c78440cd |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2014-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-eb8eb45ee83a4e99a63533f7c78440cd2025-08-20T03:10:04ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-10-011010e100441310.1371/journal.ppat.1004413The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis.Margherita BertuzziMarkus SchrettlLaura Alcazar-FuoliTimothy C CairnsAlberto MuñozLouise A WalkerSusanne HerbstMaryam SafariAngela M ChevertonDan ChenHong LiuShinobu SaijoNatalie D FedorovaDarius Armstrong-JamesCarol A MunroNick D ReadScott G FillerEduardo A EspesoWilliam C NiermanHubertus HaasElaine M BignellDestruction 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004413&type=printable |
| spellingShingle | Margherita Bertuzzi Markus Schrettl Laura Alcazar-Fuoli Timothy C Cairns Alberto Muñoz Louise A Walker Susanne Herbst Maryam Safari Angela M Cheverton Dan Chen Hong Liu Shinobu Saijo Natalie D Fedorova Darius Armstrong-James Carol A Munro Nick D Read Scott G Filler Eduardo A Espeso William C Nierman Hubertus Haas Elaine M Bignell The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis. PLoS Pathogens |
| title | 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_short | The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis. |
| title_sort | ph responsive pacc transcription factor of aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004413&type=printable |
| work_keys_str_mv | AT margheritabertuzzi thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT markusschrettl thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT lauraalcazarfuoli thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT timothyccairns thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT albertomunoz thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT louiseawalker thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT susanneherbst thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT maryamsafari thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT angelamcheverton thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT danchen thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT hongliu thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT shinobusaijo thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT nataliedfedorova thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT dariusarmstrongjames thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT carolamunro thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT nickdread thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT scottgfiller thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT eduardoaespeso thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT williamcnierman thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT hubertushaas thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT elainembignell thephresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT margheritabertuzzi phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT markusschrettl phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT lauraalcazarfuoli phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT timothyccairns phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT albertomunoz phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT louiseawalker phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT susanneherbst phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT maryamsafari phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT angelamcheverton phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT danchen phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT hongliu phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT shinobusaijo phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT nataliedfedorova phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT dariusarmstrongjames phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT carolamunro phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT nickdread phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT scottgfiller phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT eduardoaespeso phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT williamcnierman phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT hubertushaas phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis AT elainembignell phresponsivepacctranscriptionfactorofaspergillusfumigatusgovernsepithelialentryandtissueinvasionduringpulmonaryaspergillosis |