Dr. Carol Munro, Institute of Medical Sciences, University of Aberdeen
Wednesday 3rd June, 4.00 p.m., Stacey Lecture Theatre 1
The fungal cell wall is a dynamic organelle that can change composition and architecture in response to environmental signals including treatment with antifungal drugs. The cell wall of the major fungal pathogen Candida albicans is composed of chitin, beta-1,3-glucan, beta-1,6-glucan and mannoproteins. The newest class of antifungal drugs, the echinocandins,target the cell wall by inhibiting beta-1,3-glucan synthesis. The echinocandins generally provide effective therapy but sporadic breakthrough infections caused by resistant Candida isolates have been reported. C. albicans acquires echinocandin resistance through point mutations in the FKS target genes. In addition C. albicans responds to sub-MIC echinocandins by up-regulating chitin biosynthesis through activation of cell wall salvage pathways that involve PKC and calcium/calcineurin signalling. Cells with elevated chitin are less susceptible to echinocandins in vitro as well as in Candida infection models.
The response of C. albicans to cell wall damage was investigated using transcript profiling, glycoproteomics and SILAC (Stable Isotope Labelling with Amino Acids in Cell Culture). Substantial changes in the cell wall proteome in response to chemical and genetic blockade of cell wall synthesis were identified. Several predicted CAZy enzymes that are involved in modulating and cross-linking chitin and glucan (Phr1, Phr2, Pga4, Crh11, Utr2) were among the cell wall proteins (CWPs) positively regulated in response to cell wall damage. The PKC cell wall integrity pathway MAP kinase Mkc1 and the transcription factor Rlm1 were important in the regulation of these proteins. A large number of CWPs remain uncharacterised. We are determining the potential roles of these proteins in host interaction assays, drug susceptibilty and virulence using gene disruption and overexpression strategies as well as gene expression analysis. In summary, alterations in the fungal cell wall can alter the susceptibility of C. albicans to echinocandin drugs in vitro and in vivo and can affect interactions within the host.