This competitive renewal will continue to work on understanding the population genetic structures of Cryptococcus neoformans. With this massive genome sequencing data, we will expand it and add a functional and/or translational focus. Importantly, the sequence data are integrated with phenotypic data, animal models and human infection outcomes to help understand the genetic components that make it a deadly human pathogen.Cryptococcus neoformans represents a group of encapsulated basidiomycetous yeasts that continue to produce hundreds of thousands of cases of meningitis each year with mortality rates of 15 to over 50% depending on the health care systems and no new antifungal agents have been discovered for its treatment in 25 years. In this proposal, we will use whole genome sequences to direct a research platform to complete two Specific Aims that are framed in questions.
Specific Aim 1 is: What are the genotypic and phenotypic differences between clinical and environmental strains.
Specific Aim 2 examines the following question: Within clinical isolates that have already produced disease, why are some strains more virulent or aggressive than others? The goal of this proposal is three- fold. First, to use whole genome sequencing (WGS) and GWAS in a large number of strains linked to functional data in order to dial down into wild-type strains and find specific genes and/or networks important to C. neoformans fitness/survival in the mammalian host. Thus, we will identify potential weak spots in the fungus to be used for antifungal drug targets. Second, to genetically identify ?bad actor? strains producing more aggressive disease behaviors that could be identified for the treating clinician to appreciate and thus adjust treatment regimens based on this knowledge of the strain?s pathobiology. Finally, this study will create a substantial infrastructure addition of a library of well-characterized wild-type strains for use by the entire cryptococcal community for future pathobiology work.
Cryptococcal meningitis remains a major, deadly central nervous system (CNS) infection today. Despite antiretroviral therapy (ART) availability worldwide, this infection continues to produce disease and death in hundreds of thousands of patients each year. In resource-limited countries, the infection mortality rates can reach over 50% and even in resource-available health care systems, mortality rates can be between 15-30% with present treatments. The immunocompromised patient populations from AIDS to other serious underlying diseases are ?at risk? for disseminated cryptococcosis and these ?at risk? populations remain large. Furthermore, there have been no new antifungal drugs developed for treatment of cryptococcal disease in over 25 years. In this comprehensive proposal, the study of cryptococcal genes from clinical and environmental strains with ?state of the art? bioinformatics and screening assays is designed to find weak spots in the yeasts' ability to cause disease. This information can be used to discover targets for new antifungal drugs and/or identify the most pathogenic strains so clinicians can provide a more aggressive treatment strategy against them. Cryptococcal meningitis continues to cause high mortality and morbidity. It produces substantial human costs that are also linked to high specific monetary health costs. This ?fungal plague? continues and the challenge is to understand it and thus optimally manage it.
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