Gerald R. Fink, Ph.D.
Whitehead Institute for Biomedical Research

The Role of Quorum Sensing in Fungal Disease.

Fungal infections have emerged as a worldwide problem of appalling dimensions because of the AIDS epidemic. Although fungi of all types afflict immunocompromised individuals, Candida albicans is the most frequent cause of disease. One key to Candidaís pathogenesis is its ability to switch from a yeast form to a filamentous form. This switch is controlled by many environmental factors, interaction with cells of the immune system, and potentially by quorum sensing (small signaling molecules that inform microorganisms about their density). The analysis of filamentation in the model system, bakerís yeast, revealed that a key molecule required for dimorphism is an adhesin, a member of a family of cell-surface glycoproteins. These proteins are responsible both for the switch between the yeast and filamentous form, for the attachment of fungi to epithelial and endothelial cells, and for the attachment of fungal cells to each other. EDT1, one of the genes required for filament formation in Candida, appears to be regulated by cell density. The edt1 mutants fail to form filaments under many conditions that induce wild type to switch from yeast to filamentous forms. The edt1 mutant strains also show severe defects in adherence to plastic surfaces. Moreover, overstatement of EDT1 brings about filamentous growth in the absence of agents normally required for induction of filamentation. At high density the EDT1 transcript is completely stable, but at low density, the transcript level is reduced 10-fold in less than 5 minutes. Experiments will be designed to determine whether there is an extracellular factor that stabilizes the EDT1 transcript levels at high cell density. Mutants and whole genome arrays will be used to identify other genes that respond to cell density. These low/high density experiments will be performed in parallel using Saccharomyces for comparison with Candida. Genes that respond to density will be identified and their functions in filamentation and virulence determined.

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