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Calcineurin-Mediated Regulation of Hyphal Growth, Septation, and Virulence in Aspergillus fumigatus

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Abstract

Calcineurin is a heterodimeric protein phosphatase complex composed of catalytic (CnaA) and regulatory (CnaB) subunits and plays diverse roles in regulating fungal stress responses, morphogenesis, and pathogenesis. Fungal pathogens utilize the calcineurin pathway to survive in the host environment and cause life-threatening infections. The immunosuppressive calcineurin inhibitors (FK506 and cyclosporine A) are active against fungi, making calcineurin a promising antifungal drug target. Here, we review novel findings on calcineurin localization and functions in Aspergillus fumigatus hyphal growth and septum formation through regulation of proteins involved in cell wall biosynthesis. Extensive mutational analysis in the functional domains of A. fumigatus CnaA has led to an understanding of the relevance of these domains for the localization and function of CnaA at the hyphal septum. An evolutionarily conserved novel mode of calcineurin regulation by phosphorylation in filamentous fungi was found to be responsible for virulence in A. fumigatus. This finding of a filamentous fungal-specific mechanism controlling hyphal growth and virulence represents a potential target for antifungal therapy.

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Acknowledgments

These studies were funded by NIH/NIAID 1 R56 AI077648-01A2 and 1 R21 AI097541-01A1 Grants to WJS. FL is supported by the Swiss Foundation for Medical-Biological Grants and the Swiss National Science Foundation (P3SMP3-151742).

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Authors and Affiliations

  1. Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, 427 Jones Building, Research Drive, Durham, NC, 27710, USA

    Praveen R. Juvvadi, Frédéric Lamoth & William J. Steinbach

  2. Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland

    Frédéric Lamoth

  3. Institute of Microbiology, Lausanne University Hospital, Lausanne, Switzerland

    Frédéric Lamoth

  4. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA

    William J. Steinbach

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  1. Praveen R. Juvvadi
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  2. Frédéric Lamoth
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  3. William J. Steinbach
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Correspondence to Praveen R. Juvvadi or William J. Steinbach.

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Juvvadi, P.R., Lamoth, F. & Steinbach, W.J. Calcineurin-Mediated Regulation of Hyphal Growth, Septation, and Virulence in Aspergillus fumigatus . Mycopathologia 178, 341–348 (2014). https://doi.org/10.1007/s11046-014-9794-9

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  • DOI: https://doi.org/10.1007/s11046-014-9794-9

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