The fungus Candida albicans is both a significant human health burden and an emerging model system for the study of the regulation of morphological transitions. C. albicans mucosal infections in neonates, in the female reproductive tract, and in the oral- esophageal tract cause chronic morbidity. C. albicans can also cause disseminated candidiasis in compromised patients with mortality rates between 30-50%, and these infections have been reported to be the second most common cause of death from nosocomial infections (~10,000 deaths per year in the U.S.). C. albicans is optimized for growth in humans and can transition between different cellular morphologies under a range of environmental conditions. These morphological changes confer properties to the organism that facilitate its virulence, and are influenced by different environmental signals and involve multipl transcriptional regulators. Our work, and the work of others, using genetic mutants shows that Mediator, an intermediary between DNA-bound activators and the general transcription machinery in all eukaryotes, plays a major role in controlling these transitions. An emerging non-canonical view of how Mediator participates in the regulation of important physiological transitions in response to environmental cues is its direct regulation of transcription factors via its kinase activity. In this proposal, we will determine the mechanism by which the kinase activity of C. albicans Cdk8 regulates transcription factors that drive changes associated with morphology and virulence. We will also determine whether environmental signals regulate the Cdk8 kinase activity. Recent data also show that C. albicans Cdk8 is important for virulence in a murine model. The proposed research will enable our ability to fully model how complex fungal pathogen signaling pathways are regulated. In addition, since transcription factors themselves are notoriously poor drug targets, understanding how Cdk8 regulates the action of these transcription factors will help characterize a previously untapped target for potential drugs that modulate C. albicans in vivo. Because inhibitors of human Cdk8 have been shown to have great potential as therapies designed to mitigate chemotherapy resistance, it is important to understand the impact of these compounds on C. albicans, a potential pathogen in immunocompromised populations.
Fungal Pathogens, such as Candida albicans, are now the fourth leading cause of hospital-acquired bloodstream infections in the United States there is an approximately 40% mortality rate and over 10,000 deaths per year associated with systemic candidiasis. Although, anti-fungal drugs have met with some success in controlling these infections, high mortality rates indicate substantial improvement in therapies is necessary. The objective of this exploratory proposal is to determine the mechanism(s) by which the C. albicans Mediator complex enables signals from microenvironments in a human host to regulate transcriptional programs that facilitate the virulence of this important pathogen This research wil determine how inhibitors that target this kinase activity in humans, and are currently in the pipeline as cancer therapeutics, might be used as co-therapies with existing anti-fungal drugs to treat life-threatening infections.
| Liu, Zhongle; Rossi, John M; Myers, Lawrence C (2018) Candida albicans Zn Cluster Transcription Factors Tac1 and Znc1 Are Activated by Farnesol To Upregulate a Transcriptional Program Including the Multidrug Efflux Pump CDR1. Antimicrob Agents Chemother 62: |
