title: Microevolution of Candida albicans in macrophages restores filamentation in a nonfilamentous mutant.
abstract: Following antifungal treatment, Candida albicans, and other human pathogenic fungi can undergo microevolution, which leads to the emergence of drug resistance. However, the capacity for microevolutionary adaptation of fungi goes beyond the development of resistance against antifungals. Here we used an experimental microevolution approach to show that one of the central pathogenicity mechanisms of C. albicans, the yeast-to-hyphae transition, can be subject to experimental evolution. The C. albicans cph1Δ/efg1Δ mutant is nonfilamentous, as central signaling pathways linking environmental cues to hyphal formation are disrupted. We subjected this mutant to constant selection pressure in the hostile environment of the macrophage phagosome. In a comparatively short time-frame, the mutant evolved the ability to escape macrophages by filamentation. In addition, the evolved mutant exhibited hyper-virulence in a murine infection model and an altered cell wall composition compared to the cph1Δ/efg1Δ strain. Moreover, the transcriptional regulation of hyphae-associated, and other pathogenicity-related genes became re-responsive to environmental cues in the evolved strain. We went on to identify the causative missense mutation via whole genome- and transcriptome-sequencing: a single nucleotide exchange took place within SSN3 that encodes a component of the Cdk8 module of the Mediator complex, which links transcription factors with the general transcription machinery. This mutation was responsible for the reconnection of the hyphal growth program with environmental signals in the evolved strain and was sufficient to bypass Efg1/Cph1-dependent filamentation. These data demonstrate that even central transcriptional networks can be remodeled very quickly under appropriate selection pressure.
authors.affiliation: Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), Jena, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Wartenberg
authors.affiliation: Research Group Systems Biology & Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), Jena, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Linde
authors.affiliation: Septomics Research Center, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology -Hans Knoell Institute, Jena, Germany.
authors.forename: Ronny
authors.initials: R
authors.lastname: Martin
authors.affiliation: Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), Jena, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Schreiner
authors.affiliation: Research Group Systems Biology & Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), Jena, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Horn
authors.affiliation: Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), Jena, Germany; Research Group Microbial Immunology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), Jena, Germany.
authors.forename: Ilse D
authors.initials: ID
authors.lastname: Jacobsen
authors.affiliation: Medical University Vienna, Max F. Perutz Laboratories, Department of Medical Biochemistry, Vienna, Austria.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jenull
authors.affiliation: Research Group Systems Biology & Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), Jena, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wolf
authors.affiliation: Medical University Vienna, Max F. Perutz Laboratories, Department of Medical Biochemistry, Vienna, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Kuchler
authors.affiliation: Research Group Systems Biology & Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), Jena, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Guthke
authors.affiliation: Septomics Research Center, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology -Hans Knoell Institute, Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kurzai
authors.affiliation: Department of Biology, Bowdoin College, Brunswick, Maine, United States of America.
authors.forename: Anja
authors.initials: A
authors.lastname: Forche
authors.affiliation: Institut Pasteur, Unité Biologie et Pathogénicité Fongiques, Département Génomes et Génétique, Paris, France; INRA, USC2019, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: d'Enfert
authors.affiliation: Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), Jena, Germany; Integrated Research and Treatment Center, Sepsis und Sepsisfolgen, Center for Sepsis Control and Care (CSCC), Universitätsklinikum Jena, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Brunke
authors.affiliation: Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), Jena, Germany; Integrated Research and Treatment Center, Sepsis und Sepsisfolgen, Center for Sepsis Control and Care (CSCC), Universitätsklinikum Jena, Germany; Friedrich Schiller University, Jena, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hube
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000235:genetics* / Q000472:pathogenicity*; D002177:Candidiasis / Q000382:microbiology / Q000401:mortality; D002473:Cell Wall / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D019020:Directed Molecular Evolution; D015966:Gene Expression Regulation, Fungal; D014644:Genetic Variation; D025301:Hyphae / Q000235:genetics* / Q000472:pathogenicity; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D030781:Organisms, Genetically Modified; D014774:Virulence / Q000235:genetics*