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The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect

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 co...

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Autores principales: Ries, Laure Nicolas Annick, Rocha, Marina Campos, de Castro, Patrícia Alves, Silva-Rocha, Rafael, Silva, Roberto Nascimento, Freitas, Fernanda Zanolli, de Assis, Leandro José, Bertolini, Maria Célia, Malavazi, Iran, Goldman, Gustavo H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472186/
https://www.ncbi.nlm.nih.gov/pubmed/28611248
http://dx.doi.org/10.1128/mBio.00705-17
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author Ries, Laure Nicolas Annick
Rocha, Marina Campos
de Castro, Patrícia Alves
Silva-Rocha, Rafael
Silva, Roberto Nascimento
Freitas, Fernanda Zanolli
de Assis, Leandro José
Bertolini, Maria Célia
Malavazi, Iran
Goldman, Gustavo H.
author_facet Ries, Laure Nicolas Annick
Rocha, Marina Campos
de Castro, Patrícia Alves
Silva-Rocha, Rafael
Silva, Roberto Nascimento
Freitas, Fernanda Zanolli
de Assis, Leandro José
Bertolini, Maria Célia
Malavazi, Iran
Goldman, Gustavo H.
author_sort Ries, Laure Nicolas Annick
collection PubMed
description 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 MpkA(MPK1) and its associated transcription factor (TF) RlmA(RLM1), 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.
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spelling pubmed-54721862017-06-19 The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect Ries, Laure Nicolas Annick Rocha, Marina Campos de Castro, Patrícia Alves Silva-Rocha, Rafael Silva, Roberto Nascimento Freitas, Fernanda Zanolli de Assis, Leandro José Bertolini, Maria Célia Malavazi, Iran Goldman, Gustavo H. mBio Research Article 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 MpkA(MPK1) and its associated transcription factor (TF) RlmA(RLM1), 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. American Society for Microbiology 2017-06-13 /pmc/articles/PMC5472186/ /pubmed/28611248 http://dx.doi.org/10.1128/mBio.00705-17 Text en Copyright © 2017 Ries et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Ries, Laure Nicolas Annick
Rocha, Marina Campos
de Castro, Patrícia Alves
Silva-Rocha, Rafael
Silva, Roberto Nascimento
Freitas, Fernanda Zanolli
de Assis, Leandro José
Bertolini, Maria Célia
Malavazi, Iran
Goldman, Gustavo H.
The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
title The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
title_full The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
title_fullStr The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
title_full_unstemmed The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
title_short The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
title_sort aspergillus fumigatus crza transcription factor activates chitin synthase gene expression during the caspofungin paradoxical effect
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472186/
https://www.ncbi.nlm.nih.gov/pubmed/28611248
http://dx.doi.org/10.1128/mBio.00705-17
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