Mechanistic Studies and Mathematical Models for Mycolactone Toxin and Autoinhibitory WASP: Model Mechanisms for Buruli ulcer Initiation and Spread.
The Wiskott-Aldrich Syndrome Protein (WASP) has been implicated in many diseases such as Wiskott-Aldrich Syndrome (WAS) and Buruli ulcer. Mycobactrium ulcerans is the main causative organism of Buruli ulcer (BU) disease. The bacteria secretes a polyketide lipid toxin (Mycolactone). The toxin not only di uses through the cell membranes, but also binds, hijacks and disrupts the normal functions of WASP in the cytoplasm leading to over polymerization of actin lament, cytoskeletal rearrangement and eventually cell death through necrosis. In pre-ulcerative BU disease, toxins extend beyond the actual size of the lesion. A mathematical model is developed to describe the binding mechanism of the two conformations of WASP and the complexes formed using the idea of isomerization. The formulation utilizes ligand concentration-dependence (ligand-receptor), equilibrium and conservation principles. By this approach, we are able to determine the fractional response of WASP against change in concentration of its activators;
A dissertation submitted to the Department of Mathematics, Kwame Nkrumah University of science and technology in partial fulfillment of the requirement for the degree of Doctor of Philosophy in Applied Mathematics, 2015