PI, Dr. Ana Traven
Co-PI, Dr. Mary Sopta
Team members: Dr. Josipa Nemet (postdoc), Nikolina Vidan (PhD student)
Invasive fungal infections have become an important cause of mortality in immunocompromised and severely ill patients, in both the developing world and western countries. The mortality rates from these infections can reach 50% or more. Candida albicans is the most common human fungal pathogen, causing mucosal infections and systemic invasive disease. A key feature of fungi is that they are eukaryotic organisms closely related to their human host, posing a problem for the design of safe, but effective antifungal therapy.
Excitingly, we have identified a new fungal-specific factor not conserved in humans, Taf14, which represents a promising antifungal drug target. Current studies suggest that Taf14 plays a role in transcription and DNA repair, and potentially impacts on two key virulence attributes in C. albicans, adherence and filamentous growth. However, the molecular functions of this factor are unknown. Targeting Taf14 or the process it regulates would represent a completely novel approach to antifungal therapy.
In this proposal, we combine our expertise in molecular fungal pathogenesis (Traven) with transcription/DNA repair regulation (Sopta) to precisely define the molecular roles of Taf14 using the highly tractable model system S. cerevisiae, and then interrogating the virulence roles in C. albicans. We will build new fundamental knowledge of a key fungal regulator and shed light on how gene regulatory networks are orchestrated to enable genome stability and survival of a human pathogen in the face of antifungal and host immune attack. This work will be published in the very best international journals, contributing to the competitiveness of Croatian science.
Moreover, the new knowledge base that we obtain will be important for guiding the development of more effective antifungal therapy. The value of this is underscored by the fact that the global antifungal drug market is expected to reach $13.9 billion by 2018. Finally, through this collaborative project, we will build significant capacity in the area of infection and immunity in Croatia, the importance of which cannot be understated. Croatian researchers will be trained in state of the art imaging, systems biology approaches and animal models of microbial infection, all highly transferrable technologies widely applicable in the areas of cellular microbiology and immunology.
There are no current laboratories in Croatia expert in molecular mycology, and the new expertise that we will build represents an invaluable asset to the strong research in immunology in the country, with exciting potential for future collaborative projects.
Mid-term progress report
Well, we've just passed the half way point in the project and things are going as planned. We have hired two doctoral students on the project Bella Wang in the Traven lab at Monash University, Australia and Nikolina Vidan in the Sopta group at the Rudjer Bošković Institute in Zagreb, Croatia. Nikolina Vidan is currently on a six month training project in the Traven lab at Monash and both Bella and Nikolina are getting some interesting results. In addition, Nikolina Vidan has been accepted to present her data as a poster presentation at the prestigious Human Fungal Pathogens meeting to be held in France this May.
We are also now accepting applications for a post-doctoral fellow to work on the last half of the project time frame and hope to find an excellent candidate. In addition, to the work being done on Taf14 and its role in DNA repair/replicative stress, we performed a meta-analysis of existing genome wide data to examine Taf14's role in transcriptional regulation of among other things DNA damage response genes.
We found that Taf14 is required for repression of a number of genes including those responsible for the MMS induced response where Taf14 is involved in both repression and activation of these genes. This work has resulted in the recent publication of a paper in BMC Genomics, the first for this UKF project.