Investigation of the underlying mechanism by which the PKA and calcineurin pathway regulate stress tolerance in the human fungal pathogen Candida glabrata

Candida glabrata is an opportunistic fungal pathogen that often colonizes the skin and mucosal surfaces of healthy individuals. However, in immunocompromised patients, it can cause diseases leading to blood-stream, oral and vaginal infections and eventually death. A major characteristic of this species is its very high tolerance to a wide number of stresses, including antifungal stress.  Its intrinsic tolerance to fluconazole, the most used antifungal drug results in an increased incidence of this species in hospitals worldwide. High stress tolerance is often mediated by high trehalose levels (as a result of low protein kinase A activity) and by the induction of stress-related signal transduction pathways, such as the calcineurin pathway. Interestingly, in our lab we have preliminary data that show that both pathways may act together at the level of the enzyme trehalase where phosphorylation and dephosphorylation of this enzyme may result in higher or lower enzymatic activity. This will then affect the tolerance to a number of stresses. The underlying molecular mechanism will be elucidated and this may possibly result in the identification of novel antifungal drug targets, that then will be investigated in follow-up projects.