Cryptococcus neoformans is a major pathogen in immunocompetant as well as immunocompromised patients including those with AIDS in both the developed as well as the developing world. Our long-term objective is to test the hypothesis that molecular regulators of the virulence factor laccase affect the virulence of Cryptococcus neoformans. 1) Vad1 is an important regulator of mRNA stability in the fungus and had previously been shown to regulate the Mata pheromone involved in mating. During the 2014 period, we demonstrated a role for Vad1 in the regulation of autophagy by its role in modulating mRNA stability of several autophagy-dependent transcripts, extending this work to S. cerevisiae, mouse and human systems. We have also developed antibody reagents that link the target of rapamycin-dependent regulation of autophagy to this novel regulatory pathway. 2) In our work at discovering new regulators of virulence, we identified an extracellular lactonohydrolase (encoded by the LHC1 gene) that was found to modulate higher order structure of the cryptococcal capsule. This is the first description of such extracellular modification of capsule structure in a pathogen. The modification results in a more compressed capsular structure that excludes host molecules such as complement and antibody that normally are effective against invading pathogens, providing new insights as to the effectiveness of this fungal pathogen. 3) In the developing world, a lack of effective fungicidal agents currently results in over 50% mortality in cryptococcosis even after therapy. The only agent available is amphotericin, which was developed in the 1950s, is only available in intravenous formulations and is highly toxic. With a current global death rate of over 600,000 persons per year from this fungus, this is clearly unacceptable. Thus, in a collaboration with the National Center for Advancing Therapeutics (NCAT) we set out to identify potential new drugs from a library of 4000 compounds of pharmacologically active compounds. This resulted in identification of new lead compounds that are being tested further including identification of active site targets.
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