African trypanosomes: Intracellular trafficking of host defense molecules
African trypanosomes: Intracellular trafficking of host defense molecules
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DOI：
10.1111/j.1550-7408.2006.00228.x
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发表时间：
2007-01-01
影响因子：
2.2
通讯作者：
Hajduk, Stephen L.
中科院分区：
文献类型：
--
作者：
Shiflett, April M.;Faulkner, Sara D.;Hajduk, Stephen L.
布氏锥虫是牛Nagana的病原体，可感染多种哺乳动物，但不能感染人类，因为它对正常人血清的先天性细胞毒活性敏感。人高密度脂蛋白（HDL）的一个次要亚组分，包含载脂蛋白A-I（APOA 1）、载脂蛋白L-I（APOL 1）和触珠蛋白相关蛋白（HPR），提供了这种先天性保护，以对抗T。B.布氏杆菌感染HPR和APOL 1均对T细胞具有细胞毒性。B.但是当它们组装在相同的HDL中时，它们的比杀伤活性增加几百倍。这种高密度脂蛋白被称为锥虫溶解因子（TLF），可以杀死T。B.在受体结合、胞吞作用和溶酶体定位之后，对布氏杆菌进行细胞毒性。锥虫溶解因子在酸性溶酶体中被激活并促进溶酶体膜破坏。溶酶体定位是T. B. TLF杀死布鲁氏菌。布氏锥虫Rhodesiense与T. B.布鲁氏菌对TLF杀灭具有抗性，并引起人类非洲昏睡病。人类感染性T。B.罗得西亚杆菌与能够消除TLF杀伤的人血清抗性相关蛋白（SRA）的进化相关。当T. B.用SRA基因转染布氏杆菌，它变得对TLF和人血清具有高度抗性。在SRA转染的细胞中，TLF的细胞内运输被改变，并且TLF主要定位于含有细胞质囊泡的SRA的子集，而不是溶酶体。这些发现表明，TLF的细胞分布受到SRA表达的影响，并可能直接决定易感性。
Trypanosoma brucei brucei is the causative agent of Nagana in cattle and can infect a wide range of mammals but is unable to infect humans because it is susceptible to the innate cytotoxic activity of normal human serum. A minor subfraction of human high-density lipoprotein (HDL), containing apolipoprotein A-I (APOA1), apolipoprotein L-I (APOL1) and haptoglobin-related protein (HPR) provides this innate protection against T. b. brucei infection. Both HPR and APOL1 are cytotoxic to T. b. brucei but their specific activities for killing increase several hundred-fold when assembled in the same HDL. This HDL is called trypanosome lytic factor (TLF) and kills T. b. brucei following receptor binding, endocytosis, and lysosomal localization. Trypanosome lytic factor is activated in the acidic lysosome and facilitates lysosomal membrane disruption. Lysosomal localization is necessary for T. b. brucei killing by TLF. Trypanosoma brucei rhodesiense, which is indistinguishable from T. b. brucei, is resistant to TLF killing and causes human African sleeping sickness. Human infectivity by T. b. rhodesiense correlates with the evolution of a human serum resistance associated protein (SRA) that is able to ablate TLF killing. When T. b. brucei is transfected with the SRA gene it becomes highly resistant to TLF and human serum. In the SRA transfected cells, intracellular trafficking of TLF is altered and TLF mainly localizes to a subset of SRA containing cytoplasmic vesicles but not to the lysosome. These findings indicate that the cellular distribution of TLF is influenced by SRA expression and may directly determine susceptibility.