Mechanism of Trypanosoma brucei gambiense resistance to human serum

摘要

在正常情况下，血清抗寄生虫分子Apolipoprotein LI (APOL1)可针对锥虫病原体对人类提供保护。但两个“布氏锥虫”亚种rhodesiense和gambZense能抵抗APOL1,而造成几乎全部人类昏睡病病例的正是这两个亚种。这篇文章描述了T. b. gambiense抵抗APOL1的机制。其中涉及三个补充过程：APOL1吸收的降低、APOL1降解的增加和一个特定抗药因子对APOL1的“目标膜修饰”。这种抗药性在某些条件下可以被绕过，从而为针对这种寄生虫的干预措施提供了新的可能性。%The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases. T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b, brucei, the causative agent of nagana disease in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2)， which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1), Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via the trypanosome receptor TbHpHbR (ref. 5)， TLF-2 enters trypanosomes independently of TbHpHbR (refs 4， 5). APOL1 kills trypanosomes after insertion into endoso-mal/lysosomal membranes. Here we report that T. b. gambiense resists TLFs via a hydrophobic p-sheet of the T. b. gambiense-specific glycoprotein (TgsGP), which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring, cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According to such a multifactorial defence mechanism, transgenic expression of T. b. brucei TbHpHbR in T. b. gambiense did not cause parasite lysis in normal human serum. However, these transgenic parasites were killed in hypohaptoglobinaemic serum, after high TLF-1 uptake in the absence of haptoglobin (Hp) that competes for Hb and receptor binding. TbHpHbR inactivation preventing high APOL1 loading in hypohaptoglobinaemic serum may have evolved because of the overlapping endemic area of T. b. gambiense infection and malaria, the main cause of haemolysis-induced hypohap-toglobinaemia in western and central Africa.