Calcium-Mediated Induction of Paradoxical Growth following Caspofungin Treatment Is Associated with Calcineurin Activation and Phosphorylation in Aspergillus fumigatus.

Details

Serval ID
serval:BIB_6760B4E7D23F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Calcium-Mediated Induction of Paradoxical Growth following Caspofungin Treatment Is Associated with Calcineurin Activation and Phosphorylation in Aspergillus fumigatus.
Journal
Antimicrobial Agents and Chemotherapy
Author(s)
Juvvadi P.R., Muñoz A., Lamoth F., Soderblom E.J., Moseley M.A., Read N.D., Steinbach W.J.
ISSN
1098-6596 (Electronic)
ISSN-L
0066-4804
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
59
Number
8
Pages
4946-4955
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The echinocandin antifungal drug caspofungin at high concentrations reverses the growth inhibition of Aspergillus fumigatus, a phenomenon known as the "paradoxical effect," which is not consistently observed with other echinocandins (micafungin and anidulafungin). Previous studies of A. fumigatus revealed the loss of the paradoxical effect following pharmacological or genetic inhibition of calcineurin, yet the underlying mechanism is poorly understood. Here, we utilized a codon-optimized bioluminescent Ca(2+) reporter aequorin expression system in A. fumigatus and showed that caspofungin elicits a transient increase in cytosolic free Ca(2+) ([Ca(2+)]c) in the fungus that acts as the initial trigger of the paradoxical effect by activating calmodulin-calcineurin signaling. While the increase in [Ca(2+)]c was also observed upon treatment with micafungin, another echinocandin without the paradoxical effect, a higher [Ca(2+)]c increase was noted with the paradoxical-growth concentration of caspofungin. Treatments with a Ca(2+)-selective chelator, BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid], or the L-type Ca(2+) channel blocker verapamil abolished caspofungin-mediated paradoxical growth in both the wild-type and the echinocandin-resistant (EMFR-S678P) strains. Concomitant with increased [Ca(2+)]c levels at higher concentrations of caspofungin, calmodulin and calcineurin gene expression was enhanced. Phosphoproteomic analysis revealed that calcineurin is activated through phosphorylation at its serine-proline-rich region (SPRR), a domain previously shown to be essential for regulation of hyphal growth, only at a paradoxical-growth concentration of caspofungin. Our results indicate that as opposed to micafungin, the increased [Ca(2+)]c at high concentrations of caspofungin activates calmodulin-calcineurin signaling at both a transcriptional and a posttranslational level and ultimately leads to paradoxical fungal growth.
Keywords
Antifungal Agents/pharmacology, Aspergillus fumigatus/drug effects, Aspergillus fumigatus/metabolism, Calcineurin/metabolism, Calcium/metabolism, Echinocandins/pharmacology, Egtazic Acid/analogs & derivatives, Egtazic Acid/pharmacology, Fungal Proteins/metabolism, Lipopeptides/pharmacology, Phosphorylation/physiology
Pubmed
Web of science
Open Access
Yes
Create date
17/11/2015 18:38
Last modification date
20/08/2019 15:22
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