The <italic toggle="yes">Aspergillus fumigatus</italic> CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect

ABSTRACT Aspergillus fumigatus is an opportunistic fungal pathogen that causes invasive aspergillosis (IA), a life-threatening disease in immunocompromised humans. The echinocandin caspofungin, adopted as a second-line therapy in combating IA, is a β-1,3-glucan synthase inhibitor, which, when used i...

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Autores principales:	Laure Nicolas Annick Ries, Marina Campos Rocha, Patrícia Alves de Castro, Rafael Silva-Rocha, Roberto Nascimento Silva, Fernanda Zanolli Freitas, Leandro José de Assis, Maria Célia Bertolini, Iran Malavazi, Gustavo H. Goldman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Aspergillus fumigatus cell wall integrity pathway caspofungin paradoxical effect Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/924300e689a4448bbaa7ea269d50f121
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spelling	oai:doaj.org-article:924300e689a4448bbaa7ea269d50f1212021-11-15T15:51:30ZThe <italic toggle="yes">Aspergillus fumigatus</italic> CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect10.1128/mBio.00705-172150-7511https://doaj.org/article/924300e689a4448bbaa7ea269d50f1212017-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00705-17https://doaj.org/toc/2150-7511ABSTRACT Aspergillus fumigatus is an opportunistic fungal pathogen that causes invasive aspergillosis (IA), a life-threatening disease in immunocompromised humans. The echinocandin caspofungin, adopted as a second-line therapy in combating IA, is a β-1,3-glucan synthase inhibitor, which, when used in high concentrations, reverts the anticipated A. fumigatus growth inhibition, a phenomenon called the “caspofungin paradoxical effect” (CPE). The CPE has been widely associated with increased chitin content in the cell wall due to a compensatory upregulation of chitin synthase-encoding genes. Here, we demonstrate that the CPE is dependent on the cell wall integrity (CWI) mitogen-activated protein kinase MpkAMPK1 and its associated transcription factor (TF) RlmARLM1, which regulate chitin synthase gene expression in response to different concentrations of caspofungin. Furthermore, the calcium- and calcineurin-dependent TF CrzA binds to and regulates the expression of specific chitin synthase genes during the CPE. These results suggest that the regulation of cell wall biosynthetic genes occurs by several cellular signaling pathways. In addition, CrzA is also involved in cell wall organization in the absence of caspofungin. Differences in the CPE were also observed between two A. fumigatus clinical isolates, which led to the identification of a novel basic leucine zipper TF, termed ZipD. This TF functions in the calcium-calcineurin pathway and is involved in the regulation of cell wall biosynthesis genes. This study therefore unraveled additional mechanisms and novel factors governing the CPE response, which ultimately could aid in developing more effective antifungal therapies. IMPORTANCE Systemic Aspergillus fumigatus infections are often accompanied by high mortality rates. The fungal cell wall is important for infection as it has immunomodulatory and immunoevasive properties. Paradoxical growth of A. fumigatus in the presence of high concentrations of the cell wall-disturbing agent caspofungin has been observed for more than a decade, although the mechanistic nature of this phenomenon remains largely uncharacterized. Here, we show that the CWI pathway components MpkA and RlmA as well as the calcium/calcineurin-responsive transcription factor CrzA regulate the expression of cell wall biosynthetic genes during the caspofungin paradoxical effect (CPE). Furthermore, an additional, novel calcium/calcineurin-responsive transcription factor was identified to play a role in cell wall biosynthesis gene expression during the CPE. This work paints a crucial role for calcium metabolism in the CPE and provides further insight into the complex regulation of cell wall biosynthesis, which could ultimately lead to the development of more efficient antifungal therapies.Laure Nicolas Annick RiesMarina Campos RochaPatrícia Alves de CastroRafael Silva-RochaRoberto Nascimento SilvaFernanda Zanolli FreitasLeandro José de AssisMaria Célia BertoliniIran MalavaziGustavo H. GoldmanAmerican Society for MicrobiologyarticleAspergillus fumigatuscell wall integrity pathwaycaspofunginparadoxical effectMicrobiologyQR1-502ENmBio, Vol 8, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aspergillus fumigatus cell wall integrity pathway caspofungin paradoxical effect Microbiology QR1-502
spellingShingle	Aspergillus fumigatus cell wall integrity pathway caspofungin paradoxical effect Microbiology QR1-502 Laure Nicolas Annick Ries Marina Campos Rocha Patrícia Alves de Castro Rafael Silva-Rocha Roberto Nascimento Silva Fernanda Zanolli Freitas Leandro José de Assis Maria Célia Bertolini Iran Malavazi Gustavo H. Goldman The <italic toggle="yes">Aspergillus fumigatus</italic> CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
description	ABSTRACT Aspergillus fumigatus is an opportunistic fungal pathogen that causes invasive aspergillosis (IA), a life-threatening disease in immunocompromised humans. The echinocandin caspofungin, adopted as a second-line therapy in combating IA, is a β-1,3-glucan synthase inhibitor, which, when used in high concentrations, reverts the anticipated A. fumigatus growth inhibition, a phenomenon called the “caspofungin paradoxical effect” (CPE). The CPE has been widely associated with increased chitin content in the cell wall due to a compensatory upregulation of chitin synthase-encoding genes. Here, we demonstrate that the CPE is dependent on the cell wall integrity (CWI) mitogen-activated protein kinase MpkAMPK1 and its associated transcription factor (TF) RlmARLM1, which regulate chitin synthase gene expression in response to different concentrations of caspofungin. Furthermore, the calcium- and calcineurin-dependent TF CrzA binds to and regulates the expression of specific chitin synthase genes during the CPE. These results suggest that the regulation of cell wall biosynthetic genes occurs by several cellular signaling pathways. In addition, CrzA is also involved in cell wall organization in the absence of caspofungin. Differences in the CPE were also observed between two A. fumigatus clinical isolates, which led to the identification of a novel basic leucine zipper TF, termed ZipD. This TF functions in the calcium-calcineurin pathway and is involved in the regulation of cell wall biosynthesis genes. This study therefore unraveled additional mechanisms and novel factors governing the CPE response, which ultimately could aid in developing more effective antifungal therapies. IMPORTANCE Systemic Aspergillus fumigatus infections are often accompanied by high mortality rates. The fungal cell wall is important for infection as it has immunomodulatory and immunoevasive properties. Paradoxical growth of A. fumigatus in the presence of high concentrations of the cell wall-disturbing agent caspofungin has been observed for more than a decade, although the mechanistic nature of this phenomenon remains largely uncharacterized. Here, we show that the CWI pathway components MpkA and RlmA as well as the calcium/calcineurin-responsive transcription factor CrzA regulate the expression of cell wall biosynthetic genes during the caspofungin paradoxical effect (CPE). Furthermore, an additional, novel calcium/calcineurin-responsive transcription factor was identified to play a role in cell wall biosynthesis gene expression during the CPE. This work paints a crucial role for calcium metabolism in the CPE and provides further insight into the complex regulation of cell wall biosynthesis, which could ultimately lead to the development of more efficient antifungal therapies.
format	article
author	Laure Nicolas Annick Ries Marina Campos Rocha Patrícia Alves de Castro Rafael Silva-Rocha Roberto Nascimento Silva Fernanda Zanolli Freitas Leandro José de Assis Maria Célia Bertolini Iran Malavazi Gustavo H. Goldman
author_facet	Laure Nicolas Annick Ries Marina Campos Rocha Patrícia Alves de Castro Rafael Silva-Rocha Roberto Nascimento Silva Fernanda Zanolli Freitas Leandro José de Assis Maria Célia Bertolini Iran Malavazi Gustavo H. Goldman
author_sort	Laure Nicolas Annick Ries
title	The <italic toggle="yes">Aspergillus fumigatus</italic> CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
title_short	The <italic toggle="yes">Aspergillus fumigatus</italic> CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
title_full	The <italic toggle="yes">Aspergillus fumigatus</italic> CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
title_fullStr	The <italic toggle="yes">Aspergillus fumigatus</italic> CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
title_full_unstemmed	The <italic toggle="yes">Aspergillus fumigatus</italic> CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
title_sort	<italic toggle="yes">aspergillus fumigatus</italic> crza transcription factor activates chitin synthase gene expression during the caspofungin paradoxical effect
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/924300e689a4448bbaa7ea269d50f121
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The <italic toggle="yes">Aspergillus fumigatus</italic> CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect

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