Cryptococcus neoformans transcriptional regulation of the host-pathogen interface
dc.contributor.advisor | Alspaugh, J Andrew | |
dc.contributor.author | O'Meara, Teresa Rodgers | |
dc.date.accessioned | 2013-05-13T15:34:56Z | |
dc.date.available | 2013-11-09T05:30:08Z | |
dc.date.issued | 2013 | |
dc.department | Genetics and Genomics | |
dc.description.abstract | Cryptococcus neoformans is a human fungal pathogen that is also ubiquitous in the environment. To cause disease inside a human host, C. neoformans must be able to sense and respond to a multitude of stresses. One of the major responses to the host is the induction of a polysaccharide capsule, which allows the fungus to resist damage and evade the host immune response. This capsule is regulated by a number of signal transduction cascades, but a major contributor is the conserved cAMP/PKA pathway. Using genetic and molecular biology techniques, I identified Gcn5 and Rim101 as key transcriptional regulators of capsule within the host. I determined that C. neoformans Rim101 is activated by a combination of the canonical pH sensing pathway and the cAMP/PKA pathway. This novel connection potentially gives the pathogen greater flexibility in responding to environmental stimuli, thus allowing for a greater capacity for disease. I determined that the Rim101 transcription factor regulates cell wall remodeling in the context of the host by deep mRNA sequencing, electron microscopy, and biochemical assays. Using chromatin immunoprecipitation, I confirmed that these cell wall changes are under direct control of Rim101. I then confirmed the importance of cell wall changes in the host by nanoString profiling of fungal RNA in the context of a murine lung infection. I also examined the lungs of infected mice for cytokine and immune cell infiltrate and determined that C. neoformans cell wall changes are important in avoiding triggering an aberrant host response. I hypothesize that this cell wall remodeling via Rim101 activation is required for full capsule attachment and for masking immunogenic molecules from the host immune system. | |
dc.identifier.uri | ||
dc.subject | Genetics | |
dc.subject | Microbiology | |
dc.subject | Cryptococcus neoformans | |
dc.subject | Fungal pathogenesis | |
dc.subject | Transcriptional regulation | |
dc.subject | Virulence | |
dc.title | Cryptococcus neoformans transcriptional regulation of the host-pathogen interface | |
dc.type | Dissertation | |
duke.embargo.months | 6 |
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