Cryptococcal meningitis (CM) is a severe disease that affects both HIV and non-HIV infected individuals with almost a quarter of a million deaths annually globally. Despite antiviral treatment of HIV, CM continues to be a problem in the U.S. with about 6000 infections annually. Attributable mortality remains at 30-50% despite therapy and no meaningful new anti-fungal therapies have been developed in the modern era. Our long-term objective is to assess the role of host and pathogen factors in the susceptibility and outcome of cryptococcosis to improve patient outcomes. 1) Role of the RNA-binding protein DDX6 in fungal disease and autoimmunity. Our previous work characterized the role of mammalian DDX6 in the post-transcriptional regulation of autophagy, a process of cellular protein turnover that regulates the inflammasome-associated cytokine IL1B and associated this new regulatory pathway with autoimmunity in a series of patients with PIK3CD/p110 gain-of function mutations. DDX6 recruits mRNA targeted for degradation to a decapping protein, Dcp2 which removes the 5 mRNA cap, potentiating a sequence of degradation steps. Activation of Dcp2 requires phosphorylation by the target of rapamycin mTOR, which is a central regulator of innate and adaptive immunity. We have further extended these studies by showing the role of the DDX6-binding protein, PAT1 in both yeast as well as in mammalian cells as a regulator of protein synthesis. 2) New drugs for cryptococcal disease. Fungicidal activity of a drug is particularly important in cryptococcal meningitis where fungistatic drugs such as fluconazole have a 100% mortality despite therapy. We have demonstrated that an encochleated form of amphotericin B, CAMB has equal efficacy in mice to that of the traditional intravenous form of the drug without significant toxicity.
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