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

Publication ,  Journal Article
Lee, SC; Li, A; Calo, S; Inoue, M; Tonthat, NK; Bain, JM; Louw, J; Shinohara, ML; Erwig, LP; Schumacher, MA; Ko, DC; Heitman, J
Published in: Mol Microbiol
September 2015

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.

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Published In

Mol Microbiol

DOI

EISSN

1365-2958

Publication Date

September 2015

Volume

97

Issue

5

Start / End Page

844 / 865

Location

England

Related Subject Headings

  • Virulence
  • Tacrolimus
  • Spores, Fungal
  • Phagosomes
  • Mutation
  • Mucor
  • Moths
  • Models, Molecular
  • Microbiology
  • Mice
 

Citation

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MLA
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Lee, S. C., Li, A., Calo, S., Inoue, M., Tonthat, N. K., Bain, J. M., … Heitman, J. (2015). Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides. Mol Microbiol, 97(5), 844–865. https://doi.org/10.1111/mmi.13071
Lee, Soo Chan, Alicia Li, Silvia Calo, Makoto Inoue, Nam K. Tonthat, Judith M. Bain, Johanna Louw, et al. “Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides.Mol Microbiol 97, no. 5 (September 2015): 844–65. https://doi.org/10.1111/mmi.13071.
Lee, Soo Chan, et al. “Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides.Mol Microbiol, vol. 97, no. 5, Sept. 2015, pp. 844–65. Pubmed, doi:10.1111/mmi.13071.
Lee SC, Li A, Calo S, Inoue M, Tonthat NK, Bain JM, Louw J, Shinohara ML, Erwig LP, Schumacher MA, Ko DC, Heitman J. Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides. Mol Microbiol. 2015 Sep;97(5):844–865.
Journal cover image

Published In

Mol Microbiol

DOI

EISSN

1365-2958

Publication Date

September 2015

Volume

97

Issue

5

Start / End Page

844 / 865

Location

England

Related Subject Headings

  • Virulence
  • Tacrolimus
  • Spores, Fungal
  • Phagosomes
  • Mutation
  • Mucor
  • Moths
  • Models, Molecular
  • Microbiology
  • Mice