Endocytosis of a cytotoxic human high density lipoprotein results in disruption of acidic intracellular vesicles and subsequent killing of African trypanosomes.

Abstract

Abstract. The host range of Trypanosoma brucei brucei is restricted by the cytolytic effects of human serum high-density lipoprotein (HDL). The lyric activity is caused by a minor subclass of human serum HDL called trypanosome lytic factor (TLF). TLF binds in the flagellar pocket to specific TLF-binding sites. Internalization and localization of TLF to a population of endocytic vesicles, and ultimately large lysosome-like vesicles, precedes lysis of Z b. brucei.

Membrane domains and flagellar pocket boundaries are influenced by the cytoskeleton in African trypanosomes

“…This region is characterized by a narrowing of the FP at its apical end until it is little larger in diameter than the flagellum. Again, the cytoskeleton appears central to this: in particular, an electron-dense structure called the ''collar'' can be seen on the cytoplasmic side of this region, and ablation of a protein that localizes to this structure disrupts FP morphogenesis (7).Because of its central importance to pathogenicity, the endocytic activity of T. brucei has long been studied by using well-defined markers for endocytosis and subcellular compartments (1,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). These studies have established the speed, timing, and routes of uptake and traffic within the cell (1,16,18,20), but a number of critical questions remain unanswered.…”

In Vitro Generation of Human High-Density-Lipoprotein-Resistant Trypanosoma brucei brucei

“…2B, F, G, and H). We had shown previously that treatment of T. b. brucei with low concentrations of chloroquine (50 M) inhibited acidification of the lysosome, ablated TLF killing, and resulted in the accumulation of TLF in the lysosome (21,58). Therefore, even low levels of TLF uptake would be detectable under these conditions, since it would accumulate in the lysosome of the chloroquine-treated cells.…”

“…Within the acidic lysosome, TLF is activated and causes cell death. Inhibition of TLF trafficking to the lysosome or neutralization of the lysosomal pH abolishes TLF-mediated killing of T. b. brucei (13,20,21,28,30,41,49,58,70).…”

L’histoire controversée du facteur trypanolytique humain

“…Le travail pionnier de Mary Rifkin établit que ce facteur est associé à des particules d'HDL (high density lipoproteins) [2], puis différents groupes concluent que curieusement, les particules d'HDL trypanolytiques se fixent à un récepteur de surface du parasite pour être activement intériorisées par la voie endocytaire [3]. L'acidification inhérente au processus de digestion est requise pour que le facteur lyse le parasite, et le lysosome, destination finale du trafic intracellulaire, apparaît comme étant le compartiment cible de l'activité lytique [3].…”

“…Le travail pionnier de Mary Rifkin établit que ce facteur est associé à des particules d'HDL (high density lipoproteins) [2], puis différents groupes concluent que curieusement, les particules d'HDL trypanolytiques se fixent à un récepteur de surface du parasite pour être activement intériorisées par la voie endocytaire [3]. L'acidification inhérente au processus de digestion est requise pour que le facteur lyse le parasite, et le lysosome, destination finale du trafic intracellulaire, apparaît comme étant le compartiment cible de l'activité lytique [3]. Les tentatives de purification du facteur lytique concluent que ce dernier est une protéine spé-cifiquement humaine, très similaire à l'haptoglobine, l'haptoglobin-related protein ou Hpr, et le mécanisme de trypanolyse invoqué est une peroxidation de la membrane du lysosome due à l'hémoglobine (Hb) associée à l'Hpr [4].…”