African sleeping sickness is so deadly because the causative agent, Trypanosoma brucei, has a powerful array of defenses against the immune system. Because these defenses so effectively neutralize the immune system, drugs to treat sleeping sickness must kill nearly all the parasites to be curative, and vaccine development has been extremely difficult. The 5 approved treatments are lengthy and involve high doses, leading to toxic side effects and a need for significant medical infrastructure. New drugs for sleeping sickness are desperately needed, yet there are only 2 in clinical trials. The long-term goal is to understand the role of lipid metabolism in host adaptation and immune evasion, and to use this knowledge to pursue improved treatments for African sleeping sickness. The objective of this proposal is to define how fatty acid synthesis is linked to the function of the parasite's Variant Surface Glycoprotein (VSG), a lipid anchored protein that mediates all the major immune evasion mechanisms. The central hypothesis is that ongoing fatty acid synthesis is required for VSG to function in immune evasion. Our central hypothesis will be tested with two Specific Aims: (1) Examine dependence of VSG trafficking and recycling on fatty acid synthesis and (2) Examine dependence of VSG switching upon fatty acid synthesis. The general approach is to block fatty acid synthesis and assess the effect these changes have upon VSG function. The proposed research is innovative in its exploration of a novel linkage between fatty acid synthesis and immune evasion and in the provision of new reagents and tools to study antigenic variation. The proposed work is significant because it provides new understanding about the ability of T. brucei to evade the immune system, one of the major challenges to both vaccine development and to developing safe, effective treatments. The proposed work will have a positive benefit to human health by providing proof-of-concept that it is possible to target the parasite's immune evasion mechanisms, which could open up new directions in the development of safer, more effective treatments for sleeping sickness and positively affect efforts in vaccine development.
Current treatments for Trypanosoma brucei infection are inadequate, but incomplete understanding of the effect of this lethal parasite on the immune system limits both vaccine and drug development. This work will improve understanding of the parasite's immune evasion ability, and suggest ways to target this ability. This expanded knowledge of immune defense mechanisms may contribute to work in other infectious diseases.
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