African trypanosomes are parasitic protozoa which are responsible for major diseases in humans and animals. They inhabit their host's bloodstream, and evade immune defenses by antigenic variation. Antigenic variation is mediated by Variant Surface Glycoprotein (VSG), which forms a surface coat covering the entire cell. During antigenic variation the parasite synthesizes a new VSG, with a different amino acid sequence, and exchanges its old coat for a new one. It has the genetic potential to synthesize hundreds of different VSG molecules and therefore can maintain a chronic infection. The research concerns biochemical mechanisms associated with antigen variation, and many studies concern the phosphatidylinositol-containing glycolipid which is linked to the VSG and which anchors it to the plasma membrane. We will investigate the trypanosome phospholipase C, known as VSG lipase, which cleaves the glycolipid and releases VSG from the cell (possibly during antigenic variation). This enzyme is already purified to homogeneity and it is highly specific for VSG-related structures. Further studies should define its intracellular localization and may also reveal any regulatory mechanisms. Other studies are planned on the biosythesis of the glycolipid. A pre-formed glycolipid precursor has already been isolated. The next objectives will be to map the pathway by which this precursor is synthesized and to determine the mechanism by which it is covalently linked to the VSG polypeptide. Finally, studies are aimed at characterizing other processing events which occur during VSG biosynthesis. These include N-linked glycosylation and processing of the glycolipid after it is linked to the VSG. These studies may clarify biochemical mechanisms in trypanosomes which may be useful in chemotherapy against these parasites.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Physiological Chemistry Study Section (PC)
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Johns Hopkins University
Schools of Medicine
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