Caspace Activity and Virulence of Aspergillus Fumigatus

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DESCRIPTION (provided by the applicant): Infections with the opportunistic mould pathogen Aspergillus fumigatus are continuing to increase, primarily as a consequence of the rise in organ transplantation and the use of more aggressive immunosuppressive regimens. Despite some advances in antifungal therapy the prognosis for invasive aspergillosis remains poor, with mortality rates approaching 90%, emphasizing the need for new and more effective therapeutic targets for this organism. Caspase-dependent programmed cell death (PCD) is a highly conserved stress response in higher eukaryotes, and components of the apoptosis signaling machinery are considered to be among the most promising anti-cancer targets. Recent studies have shown that budding yeast have a divergent caspase that has a role in PCD, suggesting that fungal caspases may also represent potential therapeutic targets. However, the contribution of caspase activity to growth and virulence of A. fumigatus is unknown. Our preliminary data indicate that caspase activity is induced in A. fumigatus by environmental stress, and that a mutant lacking both of the caspase genes in the A. fumigatus genome is resistant to oxidative stress. The aim of this proposal is to determine the contribution of these caspase to the growth and virulence of A. fumigatus. Using mutants of A. fumigatus with deregulated caspase activity we propose to test the following hypotheses: 1. That caspase activity is required for optimal mycelial growth, particularly under conditions of stress that would be encountered in vivo. 2. That caspase activity is required for the expression of wild type virulence in a mouse model of disseminated invasive aspergillosis.