Conservation of programmed cell death across species

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PROJECT SUMMARY Genetically regulated cell death processes are critical for maintenance of human health, defense against infection and for successful cancer therapy. In contrast, long-standing assumptions in biology and prevailing evolution theories have argued against the possibility that unicellular species encode intrinsic cell death pathways. However, a turning point has occurred in recent years with advancements in evolution theory and elegant molecular-genetic studies supporting the existence of genetically programmed/regulated cell death in unicellular species, best demonstrated in prokaryotes. However, less is known about cell death mechanisms in unicellular eukaryotes, including the well-studied model yeast Saccharomyces cerevisiae. Although many yeast genes have been implicated in promoting or inhibiting yeast cell death, the detailed mechanisms of cell death in unicellular eukaryotes are unresolved relative to well-studied mammalian cell death pathways, despite the relevance of pathogenic yeast such as Cryptococcus neoformans to human health, worsened by expanding drug resistance. Cryptococcosis is a worldwide concern and the US is not spared. Aspergillosis, mucormycosis and candidiasis are also problematic infections. The arsenal of anti-fungal agents is limited and new approaches are needed. Benefits of this project could extend to agricultural pathogens and global environmental changes. Yeast appear to have multiple unconventional cell death mechanisms. Whether these mechanisms were selected during evolution, or if they can be harnessed for therapeutic benefit analogous to new anti-cancer therapies is not yet known. Here we pursue these novel cell death pathways using a yeast model system and a pathogenic yeast to determine the role of cell death-resistance in pathogenesis.