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.
Highlights
The major fungal pathogen, Candida albicans, has the capacity to colonise diverse niches in its human host
A single glutathione reductase gene has been annotated in the C. albicans genome on the basis of its sequence similarity to glutathione reductases (GRs) from other species [39]
We reasoned that key enzymes involved in the detoxification and recycling of glutathione adducts formed during oxidative stress are likely to be important for the maintenance of redox homeostasis in C. albicans and its virulence
Summary
The major fungal pathogen, Candida albicans, has the capacity to colonise diverse niches in its human host. This fungus is part of the microflora of the skin, mouth, gut and urogenital tracts of humans. C. albicans is the most common fungal species responsible for life-threatening hospital-acquired bloodstream infections in immunocompromised patients [1,2,3]. Immune cells such as macrophages combat microbial infection by exposing invading microbes to a battery of insults that include reactive nitrogen species (RNS), reactive oxygen species (ROS) and cationic fluxes [4,5,6]. C. albicans cells are exposed to significant oxidative, nitrosative and cationic stresses during host colonization and invasion [13,14,15]
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