Trypanosomes of the brucei subgroup infect a wide variety of species but only cause severe disease in some hosts (e.g. African sleeping sickness in man). Because the parasite is extracellular at all stages of infection, an understanding of the interaction of the parasite's surface with is extracellular milieu (plasma proteins, red blood cells, brain tissue, etc.) is important in elucidating the pathogenesis of the disease as well as the survival tactics of the parasite. The surface of Trypanosoma brucei is densely covered with a single surface glycoprotein (VSG). Although much is known about the structure of VSG, the detailed aspects of its attachment to the cell surface remain poorly understood. The mechanism of release of this protein from the cell, which is required at certain stages of its life cycle, or of its possible interaction with other cellular membranes has not been defined. This proposal will focus on several biochemical and biophysical aspects of the interaction of VSG with lipids in model membranes as well as with model target cell membranes (erythrocytes). Optimal conditions will be established to study the kinetics of transfer of VSG from living typanosomes to another membrane (liposomes or erythrocytes). Various parameters of the transfer process (surface charge density, ion and pH dependence) as well as possible resultant functional changes (permeability) in the traget membrane will be examined. Using a combination of techniques (electron spin resonance, a.c. calorimetry, and lipid monolayer studies) we will determine 1) the parameter which regulate the packing density of VSG in a monolayer, 2) the effect of different lipid environments on the susceptibility of VSG to phospholipase C hydrolysis, and 3) an estimate of the lateral spacing of VSG molecules in a membrane. These studies are anticipated to elucidate the underlying mechanisms involved in some biological properties of trypanosomes and the ability of these parasites to induce pathological changes in the host.
| Rifkin, M R; Landsberger, F R (1990) Trypanosome variant surface glycoprotein transfer to target membranes: a model for the pathogenesis of trypanosomiasis. Proc Natl Acad Sci U S A 87:801-5 |
