An Integrative Systems Biology approach to define the divergent kinetic responses of S. cerevisiae and C. albicans to amino acid starvation

Microbes must adapt to rapid changes in their environment if they are to survive these changes. For example, microbes must be able to adapt their metabolism to use the available nutrients, and they must adapt to nutrient limitation as these nutrients become exhausted. We are comparing how two different yeasts adapt to a particular type of nutrient limitation (amino acid starvation). We are studying bakers' yeast (Saccharomyces cerevisiae) because it is one of the best model organisms available, and because there is already a strong platform of knowledge about the amino acid starvation response in this yeast that has allowed us to build a mathematical model of this response. We are comparing bakers' yeast to Candida albicans because this is a medically important pathogen of humans that frequently causes infections in the mouth and vagina (thrush) and causes life-threatening bloodstream infections in intensive care patients. Clearly these yeasts have evolved in very different niches. Nevertheless we have shown that the pathogenic yeast C. albicans responds in roughly the same way as bakers' yeast to amino acid starvation. However, there are significant differences in the way their responses are regulated. Hence these yeasts appear to have retained a similar solution to the problem (they both make more amino acids via metabolism to overcome the shortage of amino acids), but there are differences in the control systems that regulate their adaptive responses. Both yeasts must respond rapidly to the initial nutrient starvation, but slowly turn off this starvation response as amino acids become available through metabolism. Therefore, the responses in these two yeasts must be effectively managed over time, even though their control systems differ. Our aim is to characterise these interesting differences because they will tell us about how such control systems have evolved in these yeasts. Our approach includes the building of a mathematical model that can describe the amino acid starvation response quantitatively, and that can accurately predict responses to novel experimental conditions. We have built a preliminary model. In this project we will optimise this model for bakers' yeast, and then build an equivalent model for the pathogenic yeast. These mathematical models will be very useful because they will allow us to rapidly simulate (on the computer) large numbers of experiments that are impractical to perform in the lab. This will allow us to focus our efforts in the laboratory on those experiments that are likely to be most interesting and informative. In this way we will characterise the differences between the control systems in these two yeasts. This will generate information about how these control systems have evolved, which will provide valuable messages about the evolution of microbial control systems in general.