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. ? ? ?
| Bloom, Amanda L M; Solomons, J T Graham; Havel, Virginia E et al. (2013) Uncoupling of mRNA synthesis and degradation impairs adaptation to host temperature in Cryptococcus neoformans. Mol Microbiol 89:65-83 |
| Yi, Hyun Ah; Panepinto, John C; Jacobs, Amy (2012) Inhibition of HIV entry by extracellular glucuronoxylomannan of Cryptococcus neoformans. Microb Pathog 52:25-30 |
| Zulkifli, M Naim; Kaur, Jan Naseer; Panepinto, John C (2012) Hydroxyurea enhances post-fusion hyphal extension during sexual development in C. neoformans var. grubii. Mycopathologia 173:113-9 |
| Havel, Virginia E; Wool, Nathan K; Ayad, David et al. (2011) Ccr4 promotes resolution of the endoplasmic reticulum stress response during host temperature adaptation in Cryptococcus neoformans. Eukaryot Cell 10:895-901 |
