"The C. albicans community is currently laying the foundation of understanding how this human pathogen causes infection. C. albicans infections represent a major medical and economic burden for today’s society with an estimated 400,000 blood stream infections worldwide and direct costs exceeding 1$ billion dollar a year in the U.S. alone. Although finding the biological causes of this disease seemed to be beyond our reach in the past, various aspects of the infection have been recently unveiled including its pathology, immunology, histology, and epidemiology. Here we explored the genetic components of this disease by studying the complex host-pathogen dynamics through a series of in vivo, ex vivo and in vitro experiments. By using a pathogen unbiased reverse genetic approach and a host gene candidate strategy we uncovered some of the genes and pathways that are important for pathogenicity and immunity. In particular we explored the complex host-pathogen dynamics using a C. albicans - C. elegans model system and identified four novel putative virulence factors. We focused on Zcf15, a C. albicans transcription factor that has been poorly characterized in the literature and that plays an important role in the pathogen’s ability to resist host generated reactive oxygen species (ROS). By leveraging the power of RNASeq and ChIP-Seq we identified Zcf15 transcriptional targets and DNA binding sites. These studies suggest that Zcf15 plays a critical role in carbon metabolism and that it exerts its ability to protect the pathogen from ROS by controlling the expression of thiol- peroxidases and other detoxifying enzymes. We also showed here that in C. elegans, the host’s ability to counteract the infection relies on the MAPK pathway, evidence that mirrors what has been found by others in mammals and that emphasizes the usefulness of studying C. albicans infections in smaller genetically traceable organisms like C. elegans. The nematode model is also shown here to be a powerful tool not only to study the genetic bases that drive infection and immunity but also to identify new compounds that can be used for therapeutic intervention. This model was instrumental in identifying filastatin, a small molecule that was subsequently found by our collaborators to be capable of reducing virulence in mammals. The antifungal properties of filastatin are currently undertaking further preclinical testing. Overall this thesis shed light on the complex mechanisms of C. albicans pathogenicity and host immunity and identified novel virulence determinants that can be used by the larger community for further biological studies or even drug development. "
| Identifer | oai:union.ndltd.org:wpi.edu/oai:digitalcommons.wpi.edu:etd-dissertations-1384 |
| Date | 18 September 2014 |
| Creators | Issi, Luca |
| Contributors | Reeta Rao, Advisor, Elizabeth F. Ryder, Committee Member, Luis Vidali, Committee Member, Dawn Thompson, Committee Member, Sanjay Jain, Committee Member |
| Publisher | Digital WPI |
| Source Sets | Worcester Polytechnic Institute |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Doctoral Dissertations (All Dissertations, All Years) |
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