The pathogenic fungus Cryptococcus neoformans has emerged as the primary cause of community acquired meningitis in regions of the world plagued by HIV infection. Our previous studies have demonstrated a role for post-transcriptional gene regulation in stress tolerance. Our long term goal is to systematically map the protein-RNA interactions that C. neoformans requires for the maintenance of stress tolerance and pathogenicity. We hypothesize that these RNA-protein interactions contribute to the adaptability of C. neoformans, conferring agility to gene expression independent of the nucleus. In this proposal, our focus is two-pronged: First we will identify the RNA binding protein that is interacting with a GGAUG cis element in ribosomal protein transcripts found up-regulated in the ccr4? mutant, and determine its role in stress tolerance and pathogenicity. Second, we will determine the role of the C. neoformans PUF family of RNA binding proteins in stress tolerance and pathogenicity. For both the GGAUG-binding protein and the PUF proteins, we will determine the complement of transcripts that interact with each, allowing us to assemble their respective RNA regulons. Future studies will then build on this work and expand to additional classes or RNA binding proteins. Ultimately, the identification of RNA-protein interactions important for C. neoformans stress tolerance and pathogenicity will provide us with specific targets for novel small-molecule based therapeutics.

Public Health Relevance

The long term goal of this project is to determine the RNA-protein interactions which C. neoformans requires for stress adaptation and pathogenesis. These studies will enhance our understanding of the molecular reprogramming that accompanies stress adaptation important pathogen. In defining these important RNA- protein interactions, we will determine those that will be viable targets for small-molecule therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI089920-02
Application #
8293351
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$343,774
Indirect Cost
$118,774
Name
State University of New York at Buffalo
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Bloom, Amanda L M; Panepinto, John C (2014) RNA biology and the adaptation of Cryptococcus neoformans to host temperature and stress. Wiley Interdiscip Rev RNA 5:393-406
Banerjee, Dithi; Burkard, Lauren; Panepinto, John C (2014) Inhibition of nucleotide biosynthesis potentiates the antifungal activity of amphotericin B. PLoS One 9:e87246
Glazier, Virginia E; Panepinto, John C (2014) The ER stress response and host temperature adaptation in the human fungal pathogen Cryptococcus neoformans. Virulence 5:351-6
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