The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect
Annick Ries, LN; Rocha, MC; de Castro, PA; et al.Silva-Rocha, R; Silva, RN; Freitas, FZ; de Assis, LJ; Bertolini, MC; Malavazi, I; Goldman, GH
Date: 13 June 2017
Article
Journal
MBIO
Publisher
American Society for Microbiology
Publisher DOI
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 -1,3-glucan synthase inhibitor, which, when used in high concentrations, reverts
the anticipated ...
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 -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 synthaseencoding
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.
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