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

Soo Chan Lee, Alicia Li, Silvia Calo, Makoto Inoue, Nam K Tonthat, Judith M Bain, Johanna Louw, Mari L Shinohara, Lars P Erwig, Maria A Schumacher, Dennis C Ko, Joseph Heitman

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)844-865
Number of pages22
JournalMolecular Microbiology
Volume97
Issue number5
Early online date17 Jun 2015
DOIs
Publication statusPublished - Sep 2015

Fingerprint

Host-Pathogen Interactions
Mucor
Calcineurin
Fungi
Pharmaceutical Preparations
Yeasts
Spores
Phagocytosis
Macrophages
Phagosomes
Hyphae
Antifungal Agents
Tacrolimus
Biological Products
Cyclosporine
Virulence
Catalytic Domain
Cytokines
Phenotype
Mutation

Keywords

  • Calcinerin
  • diomorphic transitions
  • antifungal transitions
  • pathogen interactions
  • Mucor cirinelloides

Cite this

Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides. / Lee, Soo Chan; Li, Alicia; Calo, Silvia; Inoue, Makoto; Tonthat, Nam K; Bain, Judith M; Louw, Johanna; Shinohara, Mari L; Erwig, Lars P; Schumacher, Maria A; Ko, Dennis C; Heitman, Joseph.

In: Molecular Microbiology, Vol. 97, No. 5, 09.2015, p. 844-865.

Research output: Contribution to journalArticle

Lee, SC, Li, A, Calo, S, Inoue, M, Tonthat, NK, Bain, JM, Louw, J, Shinohara, ML, Erwig, LP, Schumacher, MA, Ko, DC & Heitman, J 2015, 'Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides', Molecular Microbiology, vol. 97, no. 5, pp. 844-865. https://doi.org/10.1111/mmi.13071
Lee, Soo Chan ; Li, Alicia ; Calo, Silvia ; Inoue, Makoto ; Tonthat, Nam K ; Bain, Judith M ; Louw, Johanna ; Shinohara, Mari L ; Erwig, Lars P ; Schumacher, Maria A ; Ko, Dennis C ; Heitman, Joseph. / Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides. In: Molecular Microbiology. 2015 ; Vol. 97, No. 5. pp. 844-865.
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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.",
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