Endothelial Cell Injury Caused by Candida albicans Is Dependent on Iron

Abstract

Although it is known that Candida albicans causes endothelial cell injury, in vitro and in vivo, the mechanism by which this process occurs remains unknown. Iron is critical for the induction of injury in many types of host cells. Therefore, we investigated the role of iron in Candida-induced endothelial cell injury. We found that pretreatment of endothelial cells with the iron chelators phenanthroline and deferoxamine protected them from candidal injury, even though the organisms germinated and grew normally. Loading endothelial cells with iron reversed the cytoprotective effects of iron chelation. Moreover, chelation of endothelial cell iron significantly reduced phagocytosis of C. albicans by these cells, while candidal adherence to chelator-treated endothelial cells was slightly enhanced. Since endothelial cell phagocytosis of C. albicans is required for endothelial cell injury to occur, inhibition of phagocytosis is likely the principal mechanism of the cytoprotective effects of iron chelation. The production of toxic reactive oxygen intermediates by host cells is known to be inhibited by iron chelation. Therefore, we investigated whether treating endothelial cells with antioxidants could mimic the cytoprotective effects of iron chelation. Neither extracellular nor membrane-permeative antioxidants reduced candidal injury of endothelial cells. Furthermore, depleting endothelial cells of the endogenous antioxidant glutathione did not render them more susceptible to damage by C. albicans. These results suggest that candidal injury of endothelial cells is independent of the production of reactive oxygen intermediates and that the cytoprotective effects of iron chelation are not due to inhibition of the synthesis of these toxic intermediates.

Antioxidants to Prevent Bovine Neutrophil-Induced Mammary Epithelial Cell Damage

“…Furthermore, when MAC-T cells were incubated with DFO alone, no significant increase in LDH release was observed after 24 h, showing that DFO was not intrinsically toxic. This is consistent with another in vitro study performed on human endothelial cells, which reported that DFO did not increase cell susceptibility to exogenous oxidants after 48 h (Fratti et al, 1998). Furthermore, DFO has been shown to be protective in various models of ROS-induced cellular injury as reviewed by van Asbeck (1990).…”

Regulatory networks affected by iron availability in Candida albicans

“…Moreover, in the oral cavity, onset of candidiasis correlates with the progression of HIV disease (Klein et al, 1984;Dodd et al, 1991;Katz et al, 1992). Indeed, the requirement of the high-affinity iron permease (CaFtr1p) for infections in a mouse model, the requirement of siderophore transporter (Arn1p) for epithelial invasion and the iron- dependent endothelial cell injury caused by C. albicans have established a role for iron in systemic infections (Fratti et al, 1998;Ramanan and Wang, 2000;Heymann et al, 2002). This introduces the possibility that iron availability may play a role in signalling or facilitating the commensal to pathogenic transition in C. albicans.…”

Virulence genes in the pathogenic yeast Candida albicans

“…It has been shown that FTR1, a high-a¤nity iron permease localised in the cell surface, contributes to virulence in the mouse systemic model, while a second, di¡erently regulated permease, FTR2, does not [100]. FET3, a gene involved in iron uptake, is not essential for virulence but the fet3v mutant showed a reduced adherence to ¢broblasts [81], although iron is necessary for adherence to epithelial cells [101] and this mutant showed reduced growth in iron-limited medium [81]; it thus seems that other factors would be needed to transform a lack of adherence into the absence of virulence in the model tested [94,102]. Recently, RBT2, a gene encoding a putative secreted protein with similarity to ferric reductases, has been cloned in a di¡erential screen for genes overexpressed in the absence of TUP1.…”