title: Integrative Model of Oxidative Stress Adaptation in the Fungal Pathogen Candida albicans.
abstract: The major fungal pathogen of humans, Candida albicans, mounts robust responses to oxidative stress that are critical for its virulence. These responses counteract the reactive oxygen species (ROS) that are generated by host immune cells in an attempt to kill the invading fungus. Knowledge of the dynamical processes that instigate C. albicans oxidative stress responses is required for a proper understanding of fungus-host interactions. Therefore, we have adopted an interdisciplinary approach to explore the dynamical responses of C. albicans to hydrogen peroxide (H2O2). Our deterministic mathematical model integrates two major oxidative stress signalling pathways (Cap1 and Hog1 pathways) with the three major antioxidant systems (catalase, glutathione and thioredoxin systems) and the pentose phosphate pathway, which provides reducing equivalents required for oxidative stress adaptation. The model encapsulates existing knowledge of these systems with new genomic, proteomic, transcriptomic, molecular and cellular datasets. Our integrative approach predicts the existence of alternative states for the key regulators Cap1 and Hog1, thereby suggesting novel regulatory behaviours during oxidative stress. The model reproduces both existing and new experimental observations under a variety of scenarios. Time- and dose-dependent predictions of the oxidative stress responses for both wild type and mutant cells have highlighted the different temporal contributions of the various antioxidant systems during oxidative stress adaptation, indicating that catalase plays a critical role immediately following stress imposition. This is the first model to encapsulate the dynamics of the transcriptional response alongside the redox kinetics of the major antioxidant systems during H2O2 stress in C. albicans.
authors.affiliation: Institute of Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen, United Kingdom; School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Komalapriya
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Despoina
authors.initials: D
authors.lastname: Kaloriti
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Anna T
authors.initials: AT
authors.lastname: Tillmann
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Zhikang
authors.initials: Z
authors.lastname: Yin
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Carmen
authors.initials: C
authors.lastname: Herrero-de-Dios
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Mette D
authors.initials: MD
authors.lastname: Jacobsen
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Rodrigo C
authors.initials: RC
authors.lastname: Belmonte
authors.affiliation: School of Medicine and Dentistry, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Cameron
authors.affiliation: College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom.
authors.forename: Ken
authors.initials: K
authors.lastname: Haynes
authors.affiliation: Institute of Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Celso
authors.initials: C
authors.lastname: Grebogi
authors.affiliation: Institute of Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Alessandro P S
authors.initials: AP
authors.lastname: de Moura
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Neil A R
authors.initials: NA
authors.lastname: Gow
authors.affiliation: Institute of Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Thiel
authors.affiliation: Institute for Cell and Molecular Biosciences, University of Newcastle, Newcastle upon Tyne, United Kingdom.
authors.forename: Janet
authors.initials: J
authors.lastname: Quinn
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Alistair J P
authors.initials: AJ
authors.lastname: Brown
authors.affiliation: Institute of Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen, United Kingdom; School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Romano
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000975:Antioxidants / Q000378:metabolism*; D002176:Candida albicans / Q000187:drug effects / Q000502:physiology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008954:Models, Biological; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D005656:Fungal Proteins; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide