ENDOCYTOSIS OF A CYTOTOXIC HUMAN HIGH-DENSITY-LIPOPROTEIN RESULTS IN DISRUPTION OF ACIDIC INTRACELLULAR VESICLES AND SUBSEQUENT KILLING OF AFRICAN TRYPANOSOMES

The host range of Trypanosoma brucei brucei is restricted by the cytol ytic effects of human serum high-density lipoprotein (HDL). The lytic activity is caused by a minor subclass of human serum HDL called trypa nosome lytic factor (TLF). TLF binds in the flagellar pocket to specif ic TLF-binding sites. Internalization and localization of TLF to a pop ulation of endocytic vesicles, and ultimately large lysosome-like vesi cles, precedes lysis of T. b. brucei. The membranes of these large ves icles are disrupted by the accumulation of TLF particles. Inhibitor st udies with lysosomotropic amines have shown these large vesicles to be acidic in nature and that prevention of their rupture spares the cell s from TLF-mediated lysis. Furthermore, leupeptin inhibition suggests that a thioprotease may be involved in the mechanism of TLF-mediated l ysis of T. b. brucei. Based on these results, we propose a lytic mecha nism involving cell surface binding, endocytosis and lysosomal targeti ng. This is followed by lysosomal disruption and subsequent autodigest ion of the cell.