CCR4 in the Maintenance of Thermotolerance and Pathogenicity of C. Neoformans

DESCRIPTION (provided by applicant): Cryptococcus neoformans is a major cause of morbidity and mortality in patients with defects in cell mediated immunity. This research proposal sets out to investigate the role of regulated mRNA degradation in the ability of C. neoformans to survive within the host and cause disease. The overall hypothesis is that Ccr4, the catalytic component of the mRNA degradation machinery is an important regulator of thermotolerance and pathogenic fitness. The first aim sets out to assess the effect of Ccr4 deletion on thermotolerance, pathogenicity and mRNA degradation. Aim 2 will determine the role of Ccr4 in cell cycle regulation and response to replication stress under conditions that mimic conditions in the host including growth within macrophages. The third aim sets out to identify conditions that promote colocalization of Ccr4 with another regulator of pathogenic fitness, Vad1, in processing bodies, the site of mRNA degradation. This will identify conditions under which Vad1 and Ccr4 function coordinately and independently in response to stress. Ccr4 is a potential drug target, as deletion results in a severe growth defect at host temperature. This identification of cellular processes and genes regulated through this pathway has the potential for identification of novel therapeutic targets, and will provide insight into how C. neoformans is able to adapt to the stressful environment of the host and cause human disease.