ROLE AND REGULATION OF GLYCOSYLATION PATHWAYS IN LEISHMANIA PARASITES

Abstract

Leishmania are insect-borne protozoan parasites that cause a number of important diseases in humans. These parasites alternate between two major developmental stages that proliferate within the digestive tract of the sandfly vector and the phagolysosome compartment of macrophages in the mammalian host. The insect stages that initiate infection in the mammalian host are coated with a complex glycocalyx composed of GPI-anchored glycoproteins, phosphoglycans and proteophosphoglycans. Most of these molecules are shed following differentiation to the obligate intracellular stage, leaving a minimal surface coat composed of parasite and host-acquired glycolipids. In contrast, intracellular parasites accumulate an unusual class of oligosaccharides composed of β 1,2-linked mannose, that constitute the primary reserve material of these parasites. We have defined the novel pathways of mannan biosynthesis and turnover, and investigated how the pathways of cell surface and intracellular glycan biosynthesis are reciprocally regulated. We also show that the biosynthesis of these molecules in mammalian stages is dependent on gluconeogenesis and scavenging of amino acids from the macrophage phagolysosome. These analyses provide new insights into the role and regulation of different Leishmania glycosylation pathways in mammalian stages and suggest that Leishmania spp have had to adapt to life in the lysosome in order to satisfy their hexose requirements.