PROJECT SUMMARY
Programmed cell death (self-induced) is intrinsic to cellular life, including unicellular species. However, cell
death research has focused primarily on animal models to understand cancer, degenerative disorders, and
developmental processes. In contrast, there is comparably little knowledge of how prokaryotic and eukaryotic
microbes die, and cell death mechanisms in human fungal pathogens (multi- or unicellular) are nearly
unstudied. Over a million fungal infections are diagnosed annually, many causing significant mortality, and
resistance to conventional therapies continues to increase. Building on the principles of cell death discovered
in the metazoan cell death field, we propose to characterize novel cell death pathways in unicellular fungal
species using the tractable Saccharomyces cerevisiae model system. Targeted genetic approaches, cell
biological and biochemical approaches will be used to dissect a vesicle trafficking cell death pathway in yeast
that results in lysosome/vacuole membrane permeabilization and cell death, with implications for the human
pathogen Cryptococcus neoformans. This new mechanistic understanding is intended to provide fundamental
knowledge needed for the future development of new therapeutic strategies analogous to successes in
targeted cancer therapy by inducing intrinsic cell death mechanisms.