title: Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides.
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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Soo Chan
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Calo
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Nam K
authors.initials: NK
authors.lastname: Tonthat
authors.affiliation: Division of Applied Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Bain
authors.affiliation: Division of Applied Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
authors.forename: Johanna
authors.initials: J
authors.lastname: Louw
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27710, USA.|Department of Immunology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Mari L
authors.initials: ML
authors.lastname: Shinohara
authors.affiliation: Division of Applied Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK.|Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
authors.forename: Lars P
authors.initials: LP
authors.lastname: Erwig
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Schumacher
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27710, USA.|Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA.|Center for Human Genome Variation, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Ko
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
mesh_terms: D019943:Amino Acid Substitution; D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D019703:Calcineurin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D065095:Calcineurin Inhibitors / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology; D017353:Gene Deletion; D054884:Host-Pathogen Interactions; D025301:Hyphae / Q000235:genetics / Q000648:ultrastructure; D007814:Larva; D055666:Lipopeptides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D000077551:Micafungin; D051379:Mice; D008958:Models, Molecular; D009036:Moths / Q000382:microbiology; D009089:Mucor / Q000166:cytology / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D009154:Mutation; D010588:Phagosomes / Q000378:metabolism / Q000382:microbiology; D013172:Spores, Fungal / Q000472:pathogenicity; D016559:Tacrolimus / Q000494:pharmacology; D014774:Virulence / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D065095:Calcineurin Inhibitors; D016207:Cytokines; D054714:Echinocandins; D055666:Lipopeptides; C068538:liposomal amphotericin B; D000666:Amphotericin B; D019703:Calcineurin; D000077551:Micafungin; D016559:Tacrolimus