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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/eb8eb45ee83a4e99a63533f7c78440cd
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spelling	oai:doaj.org-article:eb8eb45ee83a4e99a63533f7c78440cd2021-11-25T05:45:56ZThe pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis.1553-73661553-737410.1371/journal.ppat.1004413https://doaj.org/article/eb8eb45ee83a4e99a63533f7c78440cd2014-10-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1004413https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Destruction 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.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 BignellPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 10, Iss 10, p e1004413 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 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.
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
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
title	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_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	ph-responsive pacc transcription factor of aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/eb8eb45ee83a4e99a63533f7c78440cd
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The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis.

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