This competitive renewal will continue our work on understanding the pathophysiology of cryptococcal disease in the central nervous system (CNS) from the yeast's perspective. Cryptococcus neoformans and Cryptococcus gattii represent encapsulated basidiomycetous yeasts that produce a million cases of disease per year and an estimated 600, 000 deaths with present treatment. Cryptococcus is neurotropic causing cryptococcal meningoencephalitis, the life-threatening stage of infection for this disease.
Aim 1 will not only define the in vivo transcriptional response of Cryptococcus clinical isolates to human CNS, but it will also identify gene(s) and gene pathway(s) that contribute significantly to the yeasts ability to grow and survive in the CNS. Furthermore, we will characterize these responses based on patient outcome (more or less virulent), genotype, and additional variables to identify conserved genes that may contribute to strain adaptation in the CNS to produce disease. The impact of these genes will be assessed using robust assays that examine their impact on survival in human CSF, virulence determinants, survival in animal models.
Aim 2 continues our focused analysis on how core metabolism promotes cryptococcal growth and survival in the CNS by investigating carbon and nitrogen metabolism. This application integrates advanced molecular techniques, insights of the fungus through our prior studies, and close linkage to human disease and outcome. Its goal is to dissect, identify, and validate "weak" spots in the yeast's stress response in the CNS and thus provides new target (s) for antifungal strategies, which continue to substantially fail in the treatment of this life-threatening fungal infection.
Cryptococcal meningitis occurs in approximately 1 million cases per year with an estimated mortality of 600,000 deaths per year. This is primarily related to our enlarging immunocompromised populations with HIV and transplant recipients. In resource-limited countries, the mortality can be over 50% and even in countries with advanced healthcare, mortality reaches 20-30% with present therapies. Therefore, this application attempts to understand how Cryptococcus, this encapsulated yeast, causes disease in the central nervous system. Through these studies we hope to find important genetic targets or pathways, which could be used to find new antifungal compounds for eventual drug development.
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|Inoue, Makoto; Arikawa, Tomohiro; Chen, Yu-Hsun et al. (2014) T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation. Proc Natl Acad Sci U S A 111:5295-300|
|Janbon, Guilhem; Ormerod, Kate L; Paulet, Damien et al. (2014) Analysis of the genome and transcriptome of Cryptococcus neoformans var. grubii reveals complex RNA expression and microevolution leading to virulence attenuation. PLoS Genet 10:e1004261|
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