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dc.contributor.authorBertuzzi, Margherita
dc.contributor.authorSchrettl, Markus
dc.contributor.authorAlcazar-Fuoli, Laura 
dc.contributor.authorCairns, Timothy C
dc.contributor.authorMuñoz, Alberto
dc.contributor.authorWalker, Louise A
dc.contributor.authorHerbst, Susanne
dc.contributor.authorSafari, Maryam
dc.contributor.authorCheverton, Angela M
dc.contributor.authorChen, Dan
dc.contributor.authorLiu, Hong
dc.contributor.authorSaijo, Shinobu
dc.contributor.authorFedorova, Natalie D
dc.contributor.authorArmstrong-James, Darius
dc.contributor.authorMunro, Carol A
dc.contributor.authorRead, Nick D
dc.contributor.authorFiller, Scott G
dc.contributor.authorEspeso, Eduardo A
dc.contributor.authorNierman, William C
dc.contributor.authorHaas, Hubertus
dc.contributor.authorBignell, Elaine M
dc.identifier.citationPLoS Pathog. 2014 Oct 16;10(10):e1004413es_ES
dc.description.abstractDestruction 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.es_ES
dc.description.sponsorshipThis work was supported in part by grants to EMB from the MRC (G0501164) and BBSRC (BB/G009619/1), to EMB and NDR from the Wellcome Trust (WT093596MA), to MB from Imperial College London (Division of Investigative Sciences PhD Studentship), to HH from the ERA-NET PathoGenoMics project TRANSPAT, Austrian Science Foundation (FWF I282-B09), to SGF from the National Institutes of Health, USA (R01AI073829). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.es_ES
dc.publisherPublic Library of Science (PLOS) es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshAspergillus fumigatus es_ES
dc.subject.meshEpithelial Cells es_ES
dc.subject.meshFungal Proteins es_ES
dc.subject.meshHydrogen-Ion Concentration es_ES
dc.subject.meshMice es_ES
dc.subject.meshPulmonary Aspergillosis es_ES
dc.subject.meshTranscription Factors es_ES
dc.titleThe pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosises_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderMedical Research Council (Reino Unido) 
dc.contributor.funderBiotechnology and Biological Sciences Research Council (Reino Unido) 
dc.contributor.funderWellcome Trust 
dc.contributor.funderImperial College London (Reino Unido) 
dc.contributor.funderFWF Austrian Science Fund 
dc.contributor.funderNational Institutes of Health (Estados Unidos) 
dc.identifier.journalPLoS pathogenses_ES
dc.repisalud.centroISCIII::Centro Nacional de Microbiologíaes_ES
dc.rights.accessRightsopen accesses_ES

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Atribución 4.0 Internacional
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