GLYCOSYLATION MUTANTS OF LEISHMANIA

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DESCRIPTION (provided by applicant): Parasites of the trypanosomatid protozoan genus Leishmania are responsible for a spectrum of tropical diseases, afflicting more than 10 million people worldwide; depending on the species and immune status of the infected person, this disease can be severe or fatal. In Brasil, Africa and the Mediterranean basin, leishmaniasis is a common opportunistic infection in AIDS patients, many US soldiers now stationed in the Middle East have been infected, and there is a worrisome sense that Leishmania species may be emerging or expanding in the US. The surface of the Leishmania parasite is covered by a complex carbohydrate glycocalyx, whose structure and activities are tailored to meet the parasite's needs when growing in the sand fly vector as flagellated promastigotes, or within vertebrate macrophage phagolysosome as the roundish amastigote, where it survives happily in a hostile environment and evades immune defenses. Our group and collaborators pioneered powerful methods for the generation of mutants defect in the synthesis of the surface coat, originally focusing on the abundant lipophosphoglycan (LPG) as well as structurally related carbohydrates such as proteophosphoglycan (PPG), and more recently on molecules synthesized by the action of a novel mitochondrial fucosyltransefase. These mutants define vital biosynthetic proteins required for glycoconjugate synthesis and virulence, and the study of their impact on specific aspects of the infectious cycle enables a deeper understanding of their unique vs. overlapping roles. Several of the enzymes identified show considerable promise as targets for chemotherapy, or in the development of strategies focusing on parasite vaccination and interruption of transmission.