Role of the mitotic exit network in controlling the morphological development of Candida albicans

Candida albicans is the major fungal pathogen of people. It causes superficial infections such as thrush, an irritating infection of the vagina or mouth, which affects over three quarters of women within their lifetime. It can also cause life-threatening blood stream infections in a variety of hospital patients including those on chemotherapy, suffering AIDs and those recovering from organ transplants, other surgical procedures and major burns. Mortality associated with these infections can approach 50 % even with treatment, which is higher than a wide range of bacterial infections including MRSA. A striking feature of C. albicans is its ability to grow and switch between a variety of structural or morphological forms. These different forms are often seen in samples from patients and the ability of C. albicans to switch between growth habit is known to be important for its ability to cause disease. In this project we will study the mechanisms that result in forming the different morphological forms, specifically concentrating on the genetic control of cell division which is a key difference in the range of morphological forms. This will provide important insight into how the different morphologies are formed and how cell separation is regulated. Additionally throughout the work we will also endeavour to identify new targets for the development of antifungal drugs.

Candida albicans is the most common opportunistic human fungal pathogen and causes a variety of clinical infections ranging from superficial to life-threatening systemic infections. A striking feature of C. albicans is its ability to grow in a variety of morphological forms including yeast, pseudohyphal and true hyphal forms, and the ability to switch between these morphological forms is linked to virulence. The cellular differences between the various morphological forms include the extent of polarised growth, nuclear migration, position of septation and ability to separate after cytokinesis. The control of these processes must be linked with the progression of the cell cycle. In Saccharomyces cerevisiae the exit from mitosis, entry into cytokinesis and cell separation are controlled by the Mitotic Exit Network (MEN) a GTPase regulated kinase cascade. Preliminary data suggests a similar pathway is present in C. albicans, however, it also raises questions on the role of this pathway and suggests it may act earlier in the cell cycle and be involved with yeast-hyphal morphogenesis. This project will address the role of the mitotic exit network in C. albicans and aims to reveal its regulation and function in the different morphological forms. The specific aims of the project are to assemble a collection of null or conditional mutants of MEN components in C. albicans. These would then be fully characterised through molecular genetic and cell biology approaches in order to establish the role of MEN in C. albicans. The spatial and temporal regulation of the components will also be visualised by 4D live cell imaging and the identification of protein-protein interactions. The data generated will lead to the complete understanding of the MEN in C. albicans and identify its potential role in the process of morphogenesis.