Hydrogen peroxide signalling in Candida albicans. (360G-Wellcome-089930_B_09_Z)

A major fungicidal mechanism employed by the immune system is the generation of ROS. However, the fungal pathogen Candida albicans is relatively resistant to ROS and can evade killing by macrophages. Indeed, responses to ROS are tightly linked with C. albicans virulence, yet little is known regarding the signalling mechanisms underlying such responses. Significantly, our pilot experiments revealed that the thioredoxin protein, Trx1, has vital signalling functions in C. albicans and regulates two major responses to ROS; activation of the Hog1 SAPK, and H2O2-induced filamentation. Furthermore, we find that trx1Δ cells display attenuated virulence in a mouse model of systemic candidiasis. No previous studies have identified mechanisms underlying ROS-induced filamentation, or have implicated thioredoxin in regulating a fungal SAPK pathway. Moreover, the virulence defect exhibited by trx1 cells highlights the potential importance of such processes in promoting C. albicans survival in the host. This project, which builds on a strong platform of data and combines the strengths of Newcastle and Aberdeen in C. albicans stress responses and virulence, has the following goals: to delineate the mechanisms of Trx1 regulation of the Hog1 SAPK and H2O2-induced morphogenesis and to explore which aspects of Trx1 function are important for virulence.