RNA decay links metabolism to stress adaptation in Cryptococcus neoformans
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Cryptococcus neoformans, the causative agent of cryptococcal meningitis, is an opportunistic fungal pathogen that infects immunocompromised individuals, mainly those harboring HIV. This pathogen has the potential to adapt and elicit appropriate responses to nutrient deprivation, one of the many exogenous stresses that it faces within the human body. Identifying molecules and mechanisms involved in this adaptation response is important to study pathogenesis and for implementing novel therapeutic interventions. Chapter II of this dissertation addresses the role of mRNA decay/stability in C. neoformans response to variable glucose availability and to determine the signaling partners involved in this regulatory process. We determined that Hog1 and PKA regulated ribosomal protein stability and, in turn, ribosome biogenesis in an opposing manner in response to the presence or absence of glucose. The limited use of Amphotericin B due to its high cost in resource poor settings increases the demand for developing novel antifungals. mRNA turnover is important for maintaining intracellular nucleotide homeostasis since it provides endogenous precursors for salvage pathway of nucleotide biosynthesis. Impairment of nucleotide metabolism is thus an additional stressor and this pathway can be manipulated for developing novel antifungals. Moreover, these pathways have been shown to be effective anti-parasitic, anti-viral and anti-tumor drug targets. Chapter III reveals the importance of nucleotide synthesis on Amphotericin B susceptibility in C. neoformans. We report that perturbation of de novo synthesis of nucleotides potentiate the efficacy of Amphotericin B with a more complex role of pyrimidine biosynthesis. Given the role for nucleotide sugars in the structural requirement of C. neoformans, in Chapter IV, we focused our interest on uridine biosynthetic pathway and suggested a mechanism for the synergy observed earlier, by correlating cell integrity to Amphotericin B activity in C. neoformans .