Department of Microbiology and Immunology
Eukaryotic Pathogenesis; Gene Expression; Infectious Disease; Microbial Pathogenesis; Microbiology; RNA; Signal Transduction
There are estimated to be over one million species of fungi on the earth, yet very few of these species are capable of causing deadly systemic infections in humans. One of the major limiting factors for most fungi is their inability to grow at mammalian core body temperature. We utilize the fungal pathogen Cryptococcus neoformans var. grubii as representative fungal pathogen to understand how these few fungi have adapted to growth at mammalian body temperature. C. neoformans is a worthy pathogen as it is estimated to cause over 500,000 deaths from meningoencephalitis per year, primarily in Africa and Southeast Asia as an HIV/AIDS comorbidity. We are able to utilize the temperature limited Cryptococcus amylolentus, an environmental strain that produces similar virulence factors to C. neoformans and is fully virulent in surrogate invertebrate hosts at permissive temperatures, as a comparator.
We have discovered that host temperature adaptation in C. neoformans is accompanied by a re-programming of gene expression at the level of mRNA stability. In response to temperature stress, C. neoformans rapidly degrades mRNAs encoding energy consuming machinery such as ribosomes, and prioritizes the translation of stress-responsive mRNAs on existing ribosomes. Because mRNA synthesis and decay are coupled processes, we are seeking to identify the protein components of mRNA complexes that mediate the specificity of this decay process, and post translational modifications, such as arginine methylation and phosphorylation, that modify their function. In addition, we are investigating the signaling pathways that accelerate or slow mRNA decay in response to specific environmental stimuli such as host temperature and nutrient deprivation.
Finally, mRNA decay not only alters gene expression at the post-transcriptional level, but the degradation of abundant mRNAs during stress releases nucleotide intermediates that can be utilized by the stressed cell to promote genome stability. Our work is investigating both the process of mRNA degradation as well as nucleotide metabolic pathways as drug targets in C. neoformans and other fungal pathogens.