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Mol Microbiol. 2015 Sep;97(5):844-65. doi: 10.1111/mmi.13071. Epub 2015 Jun 17.

Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides.

Author information

1
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27710, USA.
2
Department of Immunology, Duke University Medical Center, Durham, NC, 27710, USA.
3
Department of Biochemistry, Duke University Medical Center, Durham, NC, 27710, USA.
4
Division of Applied Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
5
Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
6
Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA.
7
Center for Human Genome Variation, Duke University Medical Center, Durham, NC, 27710, USA.

Abstract

Calcineurin plays essential roles in virulence and growth of pathogenic fungi and is a target of the natural products FK506 and Cyclosporine A. In the pathogenic mucoralean fungus Mucor circinelloides, calcineurin mutation or inhibition confers a yeast-locked phenotype indicating that calcineurin governs the dimorphic transition. Genetic analysis in this study reveals that two calcineurin A catalytic subunits (out of three) are functionally diverged. Homology modeling illustrates modes of resistance resulting from amino substitutions in the interface between each calcineurin subunit and the inhibitory drugs. In addition, we show how the dimorphic transition orchestrated by calcineurin programs different outcomes during host-pathogen interactions. For example, when macrophages phagocytose Mucor yeast, subsequent phagosomal maturation occurs, indicating host cells respond appropriately to control the pathogen. On the other hand, upon phagocytosis of spores, macrophages fail to form mature phagosomes. Cytokine production from immune cells differs following exposure to yeast versus spores (which germinate into hyphae). Thus, the morphogenic transition can be targeted as an efficient treatment option against Mucor infection. In addition, genetic analysis (including gene disruption and mutational studies) further strengthens the understanding of calcineurin and provides a foundation to develop antifungal agents targeting calcineurin to deploy against Mucor and other pathogenic fungi.

PMID:
26010100
PMCID:
PMC4633022
DOI:
10.1111/mmi.13071
[Indexed for MEDLINE]
Free PMC Article

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