title: Global analysis of fungal morphology exposes mechanisms of host cell escape.
abstract: Developmental transitions between single-cell yeast and multicellular filaments underpin virulence of diverse fungal pathogens. For the leading human fungal pathogen Candida albicans, filamentation is thought to be required for immune cell escape via induction of an inflammatory programmed cell death. Here we perform a genome-scale analysis of C. albicans morphogenesis and identify 102 negative morphogenetic regulators and 872 positive regulators, highlighting key roles for ergosterol biosynthesis and N-linked glycosylation. We demonstrate that C. albicans filamentation is not required for escape from host immune cells; instead, macrophage pyroptosis is driven by fungal cell-wall remodelling and exposure of glycosylated proteins in response to the macrophage phagosome. The capacity of killed, previously phagocytized cells to drive macrophage lysis is also observed with the distantly related fungal pathogen Cryptococcus neoformans. This study provides a global view of morphogenetic circuitry governing a key virulence trait, and illuminates a new mechanism by which fungi trigger host cell death.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Teresa R
authors.initials: TR
authors.lastname: O'Meara
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Amanda O
authors.initials: AO
authors.lastname: Veri
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Troy
authors.initials: T
authors.lastname: Ketela
authors.affiliation: Bioprocess Technology &Expression, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, New Jersey 07033, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, New Jersey 07033, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Roemer
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Leah E
authors.initials: LE
authors.lastname: Cowen
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000235:genetics* / Q000276:immunology / Q000648:ultrastructure; D016923:Cell Death; D002460:Cell Line; D002473:Cell Wall; D003455:Cryptococcus neoformans / Q000235:genetics* / Q000276:immunology / Q000648:ultrastructure; D025301:Hyphae / Q000235:genetics* / Q000276:immunology; D057131:Immune Evasion / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008857:Microscopy, Interference; D009024:Morphogenesis / Q000235:genetics* / Q000276:immunology; D010588:Phagosomes; D000069292:Pyroptosis / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000276:immunology / Q000648:ultrastructure
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