Polyol homeostasis and virulence in Candida albicans

DESCRIPTION (provided by applicant): Candida albicans produces large amounts of the acyclic polyols D-arabinitol and glycerol, and it accumulates these polyols intracellularly. Polyols function as intracellular osmolytes and stress protectants in other fungi, but their functions in C. albicans are not yet known. Therefore, this project's overall goals are (i) to define the mechanisms by which C. albicans regulates its intracellular polyol concentrations and (ii) to determine if C. albicans' ability to maintain polyol homeostasis is required for wild-type environmental stress tolerance and virulence. The pathway by which C. albicans catabolizes D-arabinitol is known. Therefore, Aim 1 is to elucidate the pathway by which C. albicans synthesizes D-arabinitol and to assess this pathway's functional and pathogenic significance. C. albicans mutants lacking NADPH-dependent D-ribulose reductase will be constructed and tested for D-arabinitol synthesis and catabolism, stress tolerance and virulence. Aim 2 is to elucidate the pathways by which C. albicans synthesizes and catabolizes glycerol and to assess these pathways' significance. The C. albicans homologs of the Saccharomyces cerevisiae glycerol pathway genes GPD1, GPD2, GPP1, GUT1 and GUT2 will be tested for their abilities to complement the corresponding S. cerevisiae mutations. Also, C. albicans mutants lacking these genes will be constructed and tested for glycerol synthesis and catabolism, stress tolerance and virulence. Aim 3 is to determine if the C. albicans homolog of the S. cerevisiae glycerol uptake protein Gup l p transports glycerol and D-arabinitol into the cell and if C. albicans mutants lacking Guplp are stress intolerant and/or hypovirulent. Aim 4 is to identify the plasma membrane protein that regulates efflux of intracellular polyols in C. albicans and to assess this transporter's role in polyol homeostasis, environmental stress tolerance and virulence.