title: Contribution of Fdh3 and Glr1 to Glutathione Redox State, Stress Adaptation and Virulence in Candida albicans.
abstract: The major fungal pathogen of humans, Candida albicans, is exposed to reactive nitrogen and oxygen species following phagocytosis by host immune cells. In response to these toxins, this fungus activates potent anti-stress responses that include scavenging of reactive nitrosative and oxidative species via the glutathione system. Here we examine the differential roles of two glutathione recycling enzymes in redox homeostasis, stress adaptation and virulence in C. albicans: glutathione reductase (Glr1) and the S-nitrosoglutathione reductase (GSNOR), Fdh3. We show that the NADPH-dependent Glr1 recycles GSSG to GSH, is induced in response to oxidative stress and is required for resistance to macrophage killing. GLR1 deletion increases the sensitivity of C. albicans cells to H2O2, but not to formaldehyde or NO. In contrast, Fdh3 detoxifies GSNO to GSSG and NH3, and FDH3 inactivation delays NO adaptation and increases NO sensitivity. C. albicans fdh3⎔ cells are also sensitive to formaldehyde, suggesting that Fdh3 also contributes to formaldehyde detoxification. FDH3 is induced in response to nitrosative, oxidative and formaldehyde stress, and fdh3Δ cells are more sensitive to killing by macrophages. Both Glr1 and Fdh3 contribute to virulence in the Galleria mellonella and mouse models of systemic infection. We conclude that Glr1 and Fdh3 play differential roles during the adaptation of C. albicans cells to oxidative, nitrosative and formaldehyde stress, and hence during the colonisation of the host. Our findings emphasise the importance of the glutathione system and the maintenance of intracellular redox homeostasis in this major pathogen.
authors.affiliation: Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Anna T
authors.initials: AT
authors.lastname: Tillmann
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Strijbis
authors.affiliation: Division of Applied Medicine, Mass Spectrometry Section, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Cameron
authors.affiliation: Institute for Complex Systems and Mathematical Biology, SUPA, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Elahe
authors.initials: E
authors.lastname: Radmaneshfar
authors.affiliation: Institute for Complex Systems and Mathematical Biology, SUPA, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Thiel
authors.affiliation: Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Munro
authors.affiliation: Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Donna M
authors.initials: DM
authors.lastname: MacCallum
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Ben
authors.initials: B
authors.lastname: Distel
authors.affiliation: Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Neil A R
authors.initials: NA
authors.lastname: Gow
authors.affiliation: Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Alistair J P
authors.initials: AJ
authors.lastname: Brown
mesh_terms: D000222:Adaptation, Physiological; D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002176:Candida albicans / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity; D002177:Candidiasis / Q000201:enzymology / Q000235:genetics; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D005656:Fungal Proteins; D009569:Nitric Oxide; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent; D005980:Glutathione Reductase