The role of the cross pathway control protein in the stress response and adaptation of aspergillus species to antifungals

Amarsaikhan, Nansalmaa
In this study, the adaptation and response of Aspergillus nidulans and Aspergillus fumigatus wild type and cpcA strains to antifungal compounds were studied using cultural, genetic and proteomic methods. CpcA is the fungal cross pathway control protein which may also have a role in the development of resistance to antifungal that has become a major problem in human and plant fungal diseases and many studies are devoted to address the drug resistance mechanisms. Cell adapts itself to stress when it is subjected to a stress repeatedly. The ancestor of CpcA, ATF4 (CREB2) has recently been found to be important in the survival of tumor cells after starvation and nutrient limitation and these findings are expected to open new insights into the future antifungal therapy. Fungal cross pathway control system conserves similar mechanism with the stress response pathway in humans as a response to amino acid starvation. Fungal adaptation to antifungal agents was studied using the genetic model A. nidulans with the experimentally induced adaptation setup. It was concluded that A. nidulans cells are able to adapt to antifungal. In order to understand how cell becomes resistant to a previously susceptible agent, it is important to investigate the process when the cell encounters the agent for the first time. Fungal cellular response to antifungal drugs was studied using the human opportunistic pathogen A. fumigatus at the protein level. This is the first proteomic study directed to investigate the A. fumigatus response to voriconazole (VRC). The recently developed two dimensional gel electrophoresis approach, Fluorescence 2-D Differential Gel Electrophoresis (DIGE) method was applied to visualize differentially expressed proteins. It was concluded that, about 150 proteins were differentially regulated as a response to stress exerted by azole group antifungal drugs. cpcA strains of A. nidulans and A. fumigatus were compared to wild type strains in terms of susceptibility to various stresses, adaptation potential also at the proteome level. The results obtained in this study showed that CpcA was important in the response of Aspergillus to oxidative, heat stress and in the adaptation of cells to VRC and that its absence drastically changed the cellular response to VRC at the protein level by changing the expression of about 80 proteins. Thus, this protein is a good candidate in future as a potential drug resistance mediator and further characterization is needed to elucidate its mechanism of action on drug resistance.
Citation Formats
N. Amarsaikhan, “The role of the cross pathway control protein in the stress response and adaptation of aspergillus species to antifungals,” Ph.D. - Doctoral Program, Middle East Technical University, 2010.