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.
Highlights
Micronutrients such as ferrous or cuprous ions are scarce, yet essential for life
It is a major site of iron storage, with ferric iron trapped in ferritin [33], and regulates iron fluxes in other organs through the production and excretion of the soluble hormone hepcidin [34,35]
We conclude that systemic C. albicans infection perturbs host copper homeostasis in the liver
Summary
Micronutrients such as ferrous or cuprous ions are scarce, yet essential for life. They play central roles in many biological processes, executing both structural and catalytic functions [1]. We explored the dynamics of global iron homeostasis in the host during systemic infections caused by the opportunistic fungal pathogen Candida albicans. This fungus is a commensal microbe that colonises the gut and mucosal surfaces of healthy individuals. Through the action of haem oxygenases, immune infiltrates in the kidney prevent this iron from reaching the fungal cells This generates zones of iron starvation around the fungal lesions, representing a classical nutritional immunity mechanism. Crp expression is down-regulated and Ctr high affinity copper importer is upregulated Both the efflux pump and importer are required for full fungal virulence in the mouse model, revealing the importance of dynamic host-fungal interactions during nutrient. We conclude that the maintenance of cellular copper homeostasis during periods of copper excess and subsequent starvation is essential for C. albicans virulence
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