Alistair Brown and Combinatorial Responses in Stress Pathways

BBSRC Systems Biology Grantholder Workshop, University of Nottingham, 16 December 2008.

Alistair Brown presented the CRISP (University of Aberdeen and Imperial College London) approach to studying stress responses in fungal pathogens (Combinatorial Responses in Stress Pathways).

Survival is dependent upon environmental adaptation. How do cells respond to environmental stresses? Most studies focus on responses to a specific stress. Stress responses are relatively well-characterized in the benign model yeast, S. cerevisiae. However, in nature cells are simultaneously exposed to combinations of several stressees. Therefore, a better question is how do cells respond to combinatorial stresses? Their major focus is on Candida albicans and Candida glabrata. Normally a relatively harmless commensal for humans, but can cause problems. The two are quite far apart evolutionarily. Stress responses are important for infection (evidence from microarray exps that both organisms activate stress responses when come into contact with hosts). Their focussing further on osmotic stress, oxidative stress, and nitrosative stress. Individual stress responses are complex, dynamic, and nonlinear, and interactions may be cooperative or antagonistic. Interactions are also likely to be time-and dose-dependent. It's impractical to test all possible combinations experimentally, therefore the aim is to model combinatorial responses, and then use these models to select the most informative experiments.

First, model the individual stress responses, then combine these models. Approach is to identify components of each system based on our understanding of the corresponding S.cerevisiae systems, the literature for the two systems, and bioinformatic analyses using the genome sequence. Then, identify new components of each system using advanced statistical tools based on protein seq similarity and transcriptomic datasets.

Their initial ODE modelling is based on the Klipp/Hohmann model of S.cerevisiae. Their intitial modelling is of two signalling modules regulating Hog1 in S.cerevisiae. Only the Sln1 phosphorelay is included in the Klipp model, while Ssk2 is inactive in some C.glabrata isolates. Also, the Sho1 module does not signal to Hog1 in C.albicans. They also want to build ODE and stochastic models of the two organisms, and refine the models further using wet lab experiments. They want to use qualitative reasoning to describe nodes for which innformation is sparse, and predict the nature of poorly-defined links in our models with help from theoretical biologists.

Anticipated outputs are a more complete understanding of the individual stress responses in yeasts as well as of combinatorial stress responses. Further, they wish to examine the relevance of combinatorial stress responses to fungal pathogenicity and the evolution of combinatorial stress responses.

These are just my notes and are not guaranteed to be correct. Please feel free to let me know about any errors, which are all my fault and not the fault of the speaker. 🙂

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