Novel role of the Candida albicans ferric reductase gene CFL1 in iron acquisition, oxidative stress tolerance, morphogenesis and virulence

Ferric reductase catalyzes the reduction of ferric iron into ferrous iron and plays an essential role in high-affinity iron acquisition. In this study, we found that the cfl1Δ/Δ (orf19.1263) mutant was not defective in iron acquisition. However, deletion of CFL1 increased cellular iron accumulation by elevating surface ferric reductase activity in Candida albicans, revealing that there existed functional redundancy and/or a compensatory upregulation mechanism among ferric reductase genes. The absence of CFL1 resulted in increased expression levels of other alternative ferric reductase genes, including FRP1, CFL2 and FRE10. In addition, CFL1 played an important role in the response to different oxidative stresses. Further research revealed that the cfl1Δ/Δ mutant exhibited higher levels of both ROS production and SOD activity under oxidative conditions. Moreover, deletion of CFL1 led to a profound defect in filamentous development in an iron-independent manner at both 30 and 37 °C. The cfl1Δ/Δ mutant exhibited highly attenuated virulence and reduced fungal burdens in the mouse systemic infection model, indicating that CFL1 might be a potential target for antifungal drug development. In summary, our results provide new insights into the roles of ferric reductase gene in C. albicans.