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. The specific hypothesis behind the present proposal is that a virulence associated DEAD-box protein, Vad1, identified by insertional mutagenesis, is an important regulator of laccase and virulence in C. neoformans. In 2012, we completed our work demonstrating a role for Vad1-dependent degradation of the MFalpha mating pheromone and its role in accelerating the time to successful mating using a so-called transcriptonal futile cycle. Another key signaling gene identified during the report period was a novel Specificity protein 1 (SP1) like gene that was found to regulate cell wall integrity. Cell wall integrity is critical to virulence and is a target in a number of successful anti-fungal agents including the echanocandin class of antifungals. In these studies, we identified a transcription factor, Sp1 that shows an evolutionary similarity to higher metazoans such as humans, vs. that of the yeast factor. We showed that, while the yeast factor is regulated by calcineurin, the cryptococcal factor was regulated by protein kinase C under starvation conditions as demonstrated by a dependence on this pathway for phosphorylation and nuclear translocation and is required for virulence of the organism. Previous work in our laboratory had identified cryptococcal laccase as having a role in the production of prostaglandin E2. In collaboration with S. Datta at LCID/NIAID/NIH, we found that induction of PGE2 by host and fungal pathways is important in T17 cell development and antifungal response.
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