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Mechanisms of Action: Physiological Effects

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

Praveen R. Juvvadi, Alberto Muñoz, Frédéric Lamoth, Erik J. Soderblom, M. Arthur Moseley, Nick D. Read, William J. Steinbach
Praveen R. Juvvadi
aDivision of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA
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Alberto Muñoz
bManchester Fungal Infection Group, Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom
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Frédéric Lamoth
aDivision of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA
cInfectious Diseases Service, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
dInstitute of Microbiology, Lausanne University Hospital, Lausanne, Switzerland
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Erik J. Soderblom
eDuke Proteomics Facility, Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA
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M. Arthur Moseley
eDuke Proteomics Facility, Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA
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Nick D. Read
bManchester Fungal Infection Group, Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom
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William J. Steinbach
aDivision of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA
fDepartment of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA
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DOI: 10.1128/AAC.00263-15
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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 Ca2+ reporter aequorin expression system in A. fumigatus and showed that caspofungin elicits a transient increase in cytosolic free Ca2+ ([Ca2+]c) in the fungus that acts as the initial trigger of the paradoxical effect by activating calmodulin-calcineurin signaling. While the increase in [Ca2+]c was also observed upon treatment with micafungin, another echinocandin without the paradoxical effect, a higher [Ca2+]c increase was noted with the paradoxical-growth concentration of caspofungin. Treatments with a Ca2+-selective chelator, BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid], or the L-type Ca2+ channel blocker verapamil abolished caspofungin-mediated paradoxical growth in both the wild-type and the echinocandin-resistant (EMFR-S678P) strains. Concomitant with increased [Ca2+]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 [Ca2+]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.

FOOTNOTES

    • Received 2 February 2015.
    • Returned for modification 19 May 2015.
    • Accepted 1 June 2015.
    • Accepted manuscript posted online 8 June 2015.
  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.00263-15.

  • Copyright © 2015, Juvvadi et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 Unported license.

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Calcium-Mediated Induction of Paradoxical Growth following Caspofungin Treatment Is Associated with Calcineurin Activation and Phosphorylation in Aspergillus fumigatus
Praveen R. Juvvadi, Alberto Muñoz, Frédéric Lamoth, Erik J. Soderblom, M. Arthur Moseley, Nick D. Read, William J. Steinbach
Antimicrobial Agents and Chemotherapy Jul 2015, 59 (8) 4946-4955; DOI: 10.1128/AAC.00263-15

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Calcium-Mediated Induction of Paradoxical Growth following Caspofungin Treatment Is Associated with Calcineurin Activation and Phosphorylation in Aspergillus fumigatus
Praveen R. Juvvadi, Alberto Muñoz, Frédéric Lamoth, Erik J. Soderblom, M. Arthur Moseley, Nick D. Read, William J. Steinbach
Antimicrobial Agents and Chemotherapy Jul 2015, 59 (8) 4946-4955; DOI: 10.1128/AAC.00263-15
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