Haptoglobin-hemoglobin receptor independent killing of African trypanosomes by human serum and trypanosome lytic factors
Haptoglobin-hemoglobin receptor independent killing of African trypanosomes by human serum and trypanosome lytic factors
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DOI：
10.4161/viru.3.1.18295
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发表时间：
2012-01-01
期刊：
影响因子：
5.2
通讯作者：
Hajduk, Stephen L.
中科院分区：
文献类型：
--
作者：
Bullard, Whitney;Kieft, Rudo;Hajduk, Stephen L.
非洲锥虫的触珠蛋白-血红蛋白受体（HpHbR）在人类对这些寄生虫的先天免疫中起着关键作用。该受体定位于兽医病原体布氏锥虫的鞭毛袋，与锥虫溶解因子-1（TLF-1）结合，TLF-1是人高密度脂蛋白（HDL）的一个亚类，促进内吞作用、溶酶体运输和随后的杀伤。最近，我们发现组1布氏冈比亚锥虫不表达功能性HpHbR。我们现在表明，TbbHpHbr的损失降低了T. b的易感性。布氏杆菌对人血清和TLF-1的作用分别为100倍和10，000倍。杀死缺乏HpHbR的锥虫所需的相对高浓度的人血清和TLF-1表明高亲和力TbbHpHbR结合增强了细胞毒性;然而，在不存在TbbHpHbR的情况下，其他受体或液相内吞作用足以提供一定水平的易感性。人血清含有第二种先天性免疫因子TLF-2，其已被建议独立于TbbHpHbR杀死锥虫。我们发现T。B.在TbbHpHbR缺陷型细胞中，TLF-2对布鲁氏菌的杀伤作用降低，但程度低于TLF-1。这表明TLF-1和TLF-2都可以通过TbbHpHbR摄取，但存在替代途径来摄取这些毒素。总之，本文报道的研究结果扩展了我们先前发表的研究，并表明第1组T。B.冈比亚锥虫已经进化出多种机制来避免被锥虫分解人血清因子杀死。
The haptoglobin-hemoglobin receptor (HpHbR) of African trypanosomes plays a critical role in human innate immunity against these parasites. Localized to the flagellar pocket of the veterinary pathogen Trypanosoma brucei brucei this receptor binds Trypanosome Lytic Factor-1 (TLF-1), a subclass of human high-density lipoprotein (HDL) facilitating endocytosis, lysosomal trafficking and subsequent killing. Recently, we found that group 1 Trypanosoma brucei gambiense does not express a functional HpHbR. We now show that loss of the TbbHpHbr reduces the susceptibility of T.b. brucei to human serum and TLF-1 by 100- and 10,000-fold, respectively. The relatively high concentrations of human serum and TLF-1 needed to kill trypanosomes lacking the HpHbR indicates that high affinity TbbHpHbR binding enhances the cytotoxicity; however, in the absence of TbbHpHbR, other receptors or fluid phase endocytosis are sufficient to provide some level of susceptibility. Human serum contains a second innate immune factor, TLF-2, that has been suggested to kill trypanosomes independently of the TbbHpHbR. We found that T. b. brucei killing by TLF-2 was reduced in TbbHpHbR-deficient cells but to a lesser extent than TLF-1. This suggests that both TLF-1 and TLF-2 can be taken up via the TbbHpHbR but that alternative pathways exist for the uptake of these toxins. Together the findings reported here extend our previously published studies and suggest that group 1 T. b. gambiense has evolved multiple mechanisms to avoid killing by trypanolytic human serum factors.