Molecular analysis of a glycolytic gene and the effects of glucose on Candida albicans

The human fungal pathogen Candida albicans (C. albicans) shows considerable flexibility in adapting to environmental change. C. albicans cells have evolved various defences, including specific stress responses, to evade the human immune system. This study explored the relationship between central carbon metabolism and adaptational responses of C. albicans. The first aim was to assess the attractiveness of Fbal as an antifungal target. C. albicans Fructose-1,6-bisphosphate aldolase (Fbal) is an essential metabolic enzyme required for both glycolysis and gluconeogenesis. A conditional MET3-FBA1/fba1 mutant was used to assess the role that Fbal plays in the growth and virulence of C. albicans. This revealed that Fbal enzyme levels must be reduced to less than 15% of wild type levels before the growth of this figures is inhibited. Furthermore, Fbal depletion was shown to have a fungistatic, rather than a fungicidal effect upon C. albicans growth. Also, the virulence of the MET3-FBA1/fba1 conditional mutant strain was only partially attenuated in the murine model of systemic candidiasis. Hence, Fba1 is not a particularly attractive antifungal target. The second aim was to study the effects of glucose on the C. albicans transcriptome, and to compare these with the corresponding glucose responses of S. cerevisiae. C. albicans cells exhibited a subtly different transcriptional response to glucose compared with S. cerevisiae. The responses of central metabolic genes to glucose were similar in these yeasts. However, specific stress-responsive genes were up-regulated in C. albicans in response to glucose, and this was reflected in corresponding changes in stress resistance. Thus, glucose responses are linked to certain stress responses in C. albicans. This may contribute to the success of this fungus as a human pathogen.EThOS - Electronic Theses Online ServiceGBUnited Kingdo