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Review
. 2015 Feb 25;5(1):142-65.
doi: 10.3390/biom5010142.

Oxidative stress responses in the human fungal pathogen, Candida albicans

Alessandra da Silva Dantas  1 , Alison Day  2 , Mélanie Ikeh  3 , Iaroslava Kos  4 , Beatrice Achan  5 , Janet Quinn  6
Affiliations
Review

Oxidative stress responses in the human fungal pathogen, Candida albicans

Alessandra da Silva Dantas et al. Biomolecules. .

Abstract

Candida albicans is a major fungal pathogen of humans, causing approximately 400,000 life-threatening systemic infections world-wide each year in severely immunocompromised patients. An important fungicidal mechanism employed by innate immune cells involves the generation of toxic reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. Consequently, there is much interest in the strategies employed by C. albicans to evade the oxidative killing by macrophages and neutrophils. Our understanding of how C. albicans senses and responds to ROS has significantly increased in recent years. Key findings include the observations that hydrogen peroxide triggers the filamentation of this polymorphic fungus and that a superoxide dismutase enzyme with a novel mode of action is expressed at the cell surface of C. albicans. Furthermore, recent studies have indicated that combinations of the chemical stresses generated by phagocytes can actively prevent C. albicans oxidative stress responses through a mechanism termed the stress pathway interference. In this review, we present an up-date of our current understanding of the role and regulation of oxidative stress responses in this important human fungal pathogen.

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Figures

Figure 1
Figure 1
H2O2-induced activation of Cap1 is inhibited in the presence of cations. (A) Exposure of C. albicans to H2O2 promotes the Gpx3/Ybp1-mediated oxidation and activation the Cap1 transcription factor (Cap1ox). Cap1ox can no longer interact with the Crm1 nuclear export factor resulting in its nuclear accumulation, and the subsequent Cap1-dependent induction of genes with antioxidant functions necessary for cell survival. Following cellular adaptation, Cap1ox is returned to the inactive reduced form (Cap1RED) by thioredoxin (Trx1); (B) Remarkably, when C. albicans cells are exposed to H2O2 in the presence of cations, Cap1 fails to accumulate in the nucleus and therefore antioxidant gene expression is not induced leading to cell death. This is important as, following phagocytosis, C. albicans is exposed simultaneously to ROS and cationic fluxes. See text for details.
Figure 2
Figure 2
H2O2-induced activation of the Hog1 SAPK. In response to H2O2, Hog1 becomes rapidly phosphorylated and accumulates in the nucleus, and C. albicans cells lacking Hog1 are sensitive to oxidative stress. Proteins required for H2O2-induced activation of Hog1 are shown in green. These include the response regulator Ssk1 (but no other two-component protein), the redox sensitive antioxidants Tsa1 and Trx1, and the mitochondria biogenesis factor Fzo1. Following H2O2-induced activation, Hog1 phosphorylates the Mkc1 MAPK. However, cells lacking Mkc1 are not sensitive to oxidative stress, suggesting that an, as yet, unknown Hog1 substrate(s), mediates oxidative stress resistance.
Figure 3
Figure 3
H2O2-induced activation of Rad53 triggers filamentation in C. albicans. The redox sensitive oxidoreductase Trx1 inhibits H2O2-induced activation of the DNA damage checkpoint kinase Rad53. This suggests that a regulator of Rad53 is activated by oxidation, and this active oxidised form is reduced by Trx1. Activation of the DNA damage checkpoint triggers the formation of hyperpolarised buds. See text for details.
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