title: Host-Imposed Copper Poisoning Impacts Fungal Micronutrient Acquisition during Systemic Candida albicans Infections.
abstract: Nutritional immunity is a process whereby an infected host manipulates essential micronutrients to defend against an invading pathogen. We reveal a dynamic aspect of nutritional immunity during infection that involves copper assimilation. Using a combination of laser ablation inductively coupled mass spectrometry (LA-ICP MS) and metal mapping, immunohistochemistry, and gene expression profiling from infected tissues, we show that readjustments in hepatic, splenic and renal copper homeostasis accompany disseminated Candida albicans infections in the mouse model. Localized host-imposed copper poisoning manifests itself as a transient increase in copper early in the kidney infection. Changes in renal copper are detected by the fungus, as revealed by gene expression profiling and fungal virulence studies. The fungus responds by differentially regulating the Crp1 copper efflux pump (higher expression during early infection and down-regulation late in infection) and the Ctr1 copper importer (lower expression during early infection, and subsequent up-regulation late in infection) to maintain copper homeostasis during disease progression. Both Crp1 and Ctr1 are required for full fungal virulence. Importantly, copper homeostasis influences other virulence traits-metabolic flexibility and oxidative stress resistance. Our study highlights the importance of copper homeostasis for host defence and fungal virulence during systemic disease.
authors.affiliation: Aberdeen Fungal Group, School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mackie
authors.affiliation: Aberdeen Fungal Group, School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.
authors.forename: Edina K
authors.initials: EK
authors.lastname: Szabo
authors.affiliation: Trace Element Speciation Laboratory, Department of Chemistry, College of Physical Science, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, United Kingdom.
authors.forename: Dagmar S
authors.initials: DS
authors.lastname: Urgast
authors.affiliation: Aberdeen Fungal Group, School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Ballou
authors.affiliation: Aberdeen Fungal Group, School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.
authors.forename: Delma S
authors.initials: DS
authors.lastname: Childers
authors.affiliation: Aberdeen Fungal Group, School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.
authors.forename: Donna M
authors.initials: DM
authors.lastname: MacCallum
authors.affiliation: Trace Element Speciation Laboratory, Department of Chemistry, College of Physical Science, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, United Kingdom.
authors.forename: Joerg
authors.initials: J
authors.lastname: Feldmann
authors.affiliation: Aberdeen Fungal Group, School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.
authors.forename: Alistair J P
authors.initials: AJ
authors.lastname: Brown
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000235:genetics; D002177:Candidiasis / Q000382:microbiology*; D003300:Copper / Q000378:metabolism* / Q000506:poisoning*; D004195:Disease Models, Animal; D018450:Disease Progression; D005656:Fungal Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D006706:Homeostasis; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D018384:Oxidative Stress; D013154:Spleen / Q000378:metabolism*; D014774:Virulence
chemical_list: D005656:Fungal Proteins; D003300:Copper