RNA Interference of Trypanosoma brucei Cathepsin B and L Affects Disease Progression in a Mouse Model
RNA Interference of Trypanosoma brucei Cathepsin B and L Affects Disease Progression in a Mouse Model
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DOI：
10.1371/journal.pntd.0000298
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发表时间：
2008-09-01
影响因子：
3.8
通讯作者：
McKerrow, James H.
中科院分区：
文献类型：
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作者：
Abdulla, Maha-Hamadien;O'Brien, Theresa;McKerrow, James H.
我们研究了半胱氨酸蛋白酶组织蛋白酶B和组织蛋白酶L（布氏蛋白酶）在体内小鼠模型和体外血脑屏障模型中布氏锥虫发病机制中的作用。多西环素诱导靶向组织蛋白酶B的RNAi导致寄生虫从血流中清除，并防止小鼠中的致命感染。相反，所有感染T.含有未诱导的布氏锥虫组织蛋白酶B（TbCatB）RNA构建体的布氏锥虫在第13天死亡。针对布鲁氏菌蛋白酶的RNAi诱导并没有治愈小鼠的感染;然而，这些小鼠中有50%比未诱导的对照组存活了60天。T. B.布鲁氏菌蛋白酶RNAi诱导也降低了布鲁氏菌穿过人血脑屏障的体外模型。总的来说，这些数据表明，虽然TbCatB是开发新化疗的更可能的靶点，但布鲁氏菌蛋白酶的可能作用是促进寄生虫进入大脑。
We investigated the roles played by the cysteine proteases cathepsin B and cathepsin L (brucipain) in the pathogenesis of Trypansoma brucei brucei in both an in vivo mouse model and an in vitro model of the blood-brain barrier. Doxycycline induction of RNAi targeting cathepsin B led to parasite clearance from the bloodstream and prevent a lethal infection in the mice. In contrast, all mice infected with T. brucei containing the uninduced Trypanosoma brucei cathepsin B (TbCatB) RNA construct died by day 13. Induction of RNAi against brucipain did not cure mice from infection; however, 50% of these mice survived 60 days longer than uninduced controls. The ability of T. b. brucei to cross an in vitro model of the human blood-brain barrier was also reduced by brucipain RNAi induction. Taken together, the data suggest that while TbCatB is the more likely target for the development of new chemotherapy, a possible role for brucipain is in facilitating parasite entry into the brain.