Exogenous and endogenous source of sterols in trypanosoma brucei
(1997)
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- Authors
- Supervisors
- Courtoy, Pierre Jacques
- Abstract
- The majority of protists exhibit a high and sophisticated level of intracellular compartmentalization. This specialization has arisen from the need to fulfil, within a single cell, the many diverse functions, that are carried out by distinct organs in a multicellular organism. Among trypanosomatids, this imperative is strengthened by the constraints of parasitic way of life. One obvious problem parasites have to address is the acquisition of nutrients through the cell surface, without exposure to the host humoral (Trypanosoma brucei) or lysosomal (Leishmanie spp) systems. <BR> Several transporters for sugar, amino acids and ion uptake have been demonstrated in trypanosomatids but, from the parasite’s perspective, it is the need to internalize macromolecules that brings most danger to encounter the host defences. Whereas in free-living kinetoplastids, i.e. Bodo saltans, the cytostome, or ‘mouth’, and the flagellar pocket where the flagellum emerges from the cell body are on close vicinity, in most of the trypanosomatids these two structures have apparently merged, with the notable exception f the epimastigotes of Trypanosoma cruzi. The combined cytostome and flagellar pocket apparently facilitates access to exogenous macromolecules, while extending some degree of protection to transporters or receptors required for uptake of nutrients. <BR> African tyrpanosomiasis caused by Trypanosoma brucei ad related species is a chronic disease in will and domestic animals as well as in humans. The parasites live and divide extracellularly in the blood and tissues every 5- to 7-hours. Like many parasites, T. brucei has developed a highly simplified metabolism, the price of which is an avid uptake of nutrients from the host to satisfy its rapid growth. Most of the nutrients, such as amino acids and carbohydrates, are free in the body fluids and directly permeate the trypanosome membrane by simple or facilitated diffusion, or by active transport. Other compounds are obtained from macromolecules made available by hydrolysis at the cell surface, as exemplified by nucleosides split from RNA by the plasma membrane glycosidases. In contrast, cell nutrients such as cholesterol or metals circulate tightly bound to carrier proteins and can only be used in eukaryotic cells after endocytosis of their respective transport protein and intracellular release. Many types of eukaryotic cells exploit receptor-mediated endocytosis for the efficient uptake of low-density lipoprotein (LDL) articles or transferring. T. brucei, although having diverged from other eukaryotes about one billion years ago, utilizes in its mammalian stage such carrier proteins from its various hosts, thanks to its own specific receptors. These exposed receptors have received increasing interest over the last years, based not only on evidence for an essential role in optimal parasite growth, but also on the likely assumption of structural constrains, reflected in conserved epitopes. In a context of ever evolving surface coat antigens, invariant epitopes could represent potential targets for a humoral immune response. <BR> The first section of this thesis summarizes in the form of a short review, the biological and immunological properties of LDL-receptors in T. brucei, and their role in lipid import. We focus on bloodstream forms and discuss procyclic forms, living in the midgut of the insect vector, for comparative purposes. Our results demonstrate than the bloodstream forms of T; brucei do not synthesize de novo sterols and fatty acids and therefore cannot survive in medium devoid of lipoproteins. These forms show receptor-mediated endocytosis of host LDL via the flagellar pocket. LDL receptors are crucial in supply of phospholipids and cholesteryl esters that are released from internalized LDL once degraded by acidic thiol-proteases. In bloodstream forms, these exogenous lipids are then processed and metabolized similarly as in mammalian cells. In contrast to bloodstream forms, procyclic forms may acquire sterols from both exogenous (by lipoprotein endocytosis) and endogenous (by internal biosynthesis of ergosterol) sources. These two pathways complement each other, with a fine balance in sterol supply, indicating adaptative capacities to survive in quite different environments and regulatory mechanisms to ensure sterol homeostasis. <BR> We show that in bloodstream forms, pharmacological or immunological interference with the various events underlying receptor-mediated endocytosis of LDL, lysosomal degradation and the subsequent events leading to utilization of lipid metabolites, could open new approaches to fight against these parasites. Moreover, the LDL receptor of bloodstream forms may represent a potential target for a humoral immune response. Indeed, the LDL receptor is an invariant antigen that bears distinct epitopes, recycles ot the cell surface, induces complement-mediated lysis and seems to participate in the immunity of trypanotolerant animals. <BR> The second section includes our key published contributions on : <BR> - the characterization of LDL-recpetors in Trypanosoma brucei; <BR> - the intracellular fate of LDL particles and LDL-receptors; <BR> - the lipid supply from exogenous and endogenous sources; <BR> - LDL-receptors as non variant surface antigens
- Affiliations
Citations
Coppens, I. (1997). Exogenous and endogenous source of sterols in trypanosoma brucei. https://hdl.handle.net/2078.5/112129