Iron at the Centre of Candida albicans Interactions

Abstract

Iron is an absolute requirement for both the host and most pathogens alike and is needed for normal cellular growth. The acquisition of iron by biological systems is regulated to circumvent toxicity of iron overload, as well as the growth deficits imposed by iron deficiency. In addition, hosts, such as humans, need to limit the availability of iron to pathogens. However, opportunistic pathogens such as Candida albicans are able to adapt to extremes of iron availability, such as the iron replete environment of the gastrointestinal tract and iron deficiency during systemic infection. C. albicans has developed a complex and effective regulatory circuit for iron acquisition and storage to circumvent iron limitation within the human host. As C. albicans can form complex interactions with both commensal and pathogenic co-inhabitants, it can be speculated that iron may play an important role in these interactions. In this review, we highlight host iron regulation as well as regulation of iron homeostasis in C. albicans. In addition, the review argues for the need for further research into the role of iron in polymicrobial interactions. Lastly, the role of iron in treatment of C. albicans infection is discussed.

Keywords: Candida albicans; host; interaction; iron; polymicrobial; regulation; treatment.

Figure 1

Schematic of the iron uptake mechanisms of Candida albicans. Iron can be acquired from host iron binding proteins such as hemoglobin (Kuznets et al., 2014), ferritin (Almeida et al., 2008), and transferrin, as well as from free iron through the action of the reductive iron uptake pathway (Knight et al., 2002, 2005). In addition, the siderophore uptake system (Sit1/Arn1) functions in iron acquisition from xenosiderophores (Heymann et al., 2002).

Figure 2

Regulation of iron homeostasis in Candida albicans. During iron depleted conditions, Sef1 is induced and activated by Ssn3 (Chen and Noble, 2012), and induces the expression of HAP43 and iron acquisition genes (Chen et al., 2011). In turn, Hap43 also induces iron acquisition genes, as well as repression of iron utilization genes and Sfu1 (Singh et al., 2011). During conditions of replete iron, repression of Sfu1 expression is lifted. This leads to inhibition of Sef1 expression and nuclear localization, as well as repression of iron acquisition genes (Lan et al., 2004). Iron replete conditions can also promote methylation of DNA that can lead to repression of iron acquisition genes (Mishra et al., 2011).