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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI021334-06
Application #
3131330
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1984-05-01
Project End
1992-04-30
Budget Start
1989-05-01
Budget End
1990-04-30
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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