Rule Based Modeling of Iron Homeostasis in Tuberculosis

Conference poster, 2010

Mycobacterium tuberculosis (Mtb), which causes Tuberculosis (TB), has evolved into many drug resistant forms, and in symbiosis with AIDS and other diseases, has become a dreaded pathogen world-wide. In an attempt to find new drugs, researchers have turned to the study of iron homeostasis in TB: iron is an important resource that Mtb steals from its host, and is involved in the manifestation of virulence. We have formally encoded the relevant molecular interactions described in the literature, yielding a program to simulate these aspects of iron metabolism in Mtb, in the host, and in the interaction between the two. Iron acquisition via siderophores is featured in detail. The Kappa modeling language we use represents molecular interactions compactly by rules, these being generalisations of chemical equations. The Kappa tool tells us syntactically how the reactions are related, so we can see which play a central role, and which are comparatively isolated. Our simulation results, both pathways and concentrations of species, match those described in the literature. Our program can therefore be used as an unambiguous representation to anchor discussions about iron and TB, and to predict the results of hypothetical perturbations that might be of use in the search for new drugs. For example, the results of changing the infection level are as expected. A future possibility would be to combine our model with a genetic algorithm to suggest ways in which Mtb might evolve resistance to planned interventions.