Humans and some primates are naturally resistant to the cattle parasite T. brucei because of a serum factor that lyses the parasite. This trypanolytic activity has been demonstrated to be associated with high density lipoprotein (HDL) particles (reviewed in 1). These particles consist of lipids and several proteins collectively known as apolipoproteins. African trypanosomes take up these particles via receptor-mediated endocytosis and this uptake is important in regards to the toxicity (2). Two proteins found in HDL particles have been proposed to be the trypanolytic factor: haptoglobin-related protein (HRP) and apolipoprotein L1 (ApoL1).
HRP has been demonstrated to have trypanolytic activity (3). Furthermore, characterization of sera from primates which do and do not lyse trypanosomes shows a correlation between lytic activity and the presence of HRP (4). HRP results from a gene duplication of haptoglobin which is only found in humans and some other primates. Haptoglobin is a serum protein which functions to bind hemoglobin. One hypothesis is that the HRP-hemoglobin complex is taken up by the trypanosome via receptor-medicated endocytosis. Fusion of these coated vesicles with the lysosome would result in a lower pH which could stimulate the production of free radicals by the HRP-hemoglobin complex. The free radicals would then damage the membranes of the lysosome and release hydrolytic enzymes into the parasite cytoplasm leading to parasite lysis and death. However, questions about whether HRP actually binds hemoglobin have been raised. In addition, no direct evidence for a role of peroxidative mechanisms could be shown for TLF-mediated lysis (5).
Because of these problems others have proposed that ApoL1 may by the trypanosome lytic factor. ApoL1 has also been demonstrated to be taken up by trypanosomes and targeted to the lysosomes (6). ApoL1 contains a pore-forming domain and is capable of forming pores on the lysosomal membrane (7). This results in a depolarization of the lysosome due to an influx of chloride ions and the accompanying water and osmotic swelling of the lysosomes. The continual enlargement of the lysosome and osmotic changes may lead to parasite lysis. A synergy between HRP, ApoL1 and other HDL components has also been suggested (10). Subsequently, it was shown that HRP facilitates the uptake of HDL particles and does not directly participate in the lysis of the trypanosomes (11).
T. gambiense and T. rhodesiense are resistant to the trypanosome lytic factor found in human serum. One possible mechanism of this resistance to human serum is a decrease receptor-mediated endocytosis of HDL by the trypanosome (2). In addition, a serum resistance associate (SRA) gene has been described in T. rhodesiense (8,9). SRA is a truncated variant surface glycoprotein (VSG) and is localized to the lysosome. Furthermore, SRA binds to ApoL1 in the lysosome and this interaction is believed to neutralize the toxic effect of apoL-1 (6), thus suggesting that ApoL1 is TLF. However, the SRA gene is only found in T. rhodesiense, and not T. gambiense, suggesting that there are multiple mechanisms for human infectivity.