Identifying host regulators and inhibitors of liver stage malaria infection using kinase activity profiles.
Identifying host regulators and inhibitors of liver stage malaria infection using kinase activity profiles.
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DOI：
10.1038/s41467-017-01345-2
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发表时间：
2017-11-01
影响因子：
16.6
通讯作者：
Kaushansky A
中科院分区：
文献类型：
--
作者：
Arang N;Kain HS;Glennon EK;Bello T;Dudgeon DR;Walter ENF;Gujral TS;Kaushansky A
疟原虫在感染的专性肝阶段对宿主肝细胞有广泛的需求，但对特定宿主调节因子的了解仍然很少。在这里，我们评估了34种宿主靶向激酶抑制剂消除约氏疟原虫感染肝细胞的能力。使用预先存在的活性曲线的每个抑制剂，我们生成一个预测的计算模型，识别宿主激酶，这有利于约氏疟原虫肝脏阶段感染。我们预测了47种激酶，包括新的和以前描述的影响感染的激酶。通过实验验证了激酶子集的影响，包括受体酪氨酸激酶、MAP激酶级联成员和WEE 1。我们的方法还预测了感染的宿主靶向激酶抑制剂，包括已经用于人类的化合物。这些化合物中的三种，VX-680，Roscovitine和舒尼替尼，每个消除>85%的感染。我们的方法非常适合于发现困难模型系统中感染的关键宿主决定因素，包括现场分离的寄生虫和/或新出现的病原体。宿主激酶促进疟原虫肝期（LS）感染，但缺乏系统的会计重要球员。在这里，作者使用计算方法和激酶活性谱来鉴定LS感染的宿主激酶调节剂和可以消除寄生虫负担的药物。
Plasmodium parasites have extensive needs from their host hepatocytes during the obligate liver stage of infection, yet there remains sparse knowledge of specific host regulators. Here we assess 34 host-targeted kinase inhibitors for their capacity to eliminate Plasmodium yoelii-infected hepatocytes. Using pre-existing activity profiles of each inhibitor, we generate a predictive computational model that identifies host kinases, which facilitate Plasmodium yoelii liver stage infection. We predict 47 kinases, including novel and previously described kinases that impact infection. The impact of a subset of kinases is experimentally validated, including Receptor Tyrosine Kinases, members of the MAP Kinase cascade, and WEE1. Our approach also predicts host-targeted kinase inhibitors of infection, including compounds already used in humans. Three of these compounds, VX-680, Roscovitine and Sunitinib, each eliminate >85% of infection. Our approach is well-suited to uncover key host determinants of infection in difficult model systems, including field-isolated parasites and/or emerging pathogens. Host kinases facilitate Plasmodium liver stage (LS) infection, but systematic accounting of important players is lacking. Here, the authors use a computational approach and kinase activity profiles to identify host kinase regulators of LS infection and drugs that could eliminate parasite burden.
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影响因子：
64.5
作者：
Gujral TS;Chan M;Peshkin L;Sorger PK;Kirschner MW;MacBeath G
通讯作者：
MacBeath G
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
64.5
作者：
Hsu PD;Lander ES;Zhang F
通讯作者：
Zhang F
DOI：
10.1073/pnas.1403080111
发表时间：
2014-04-01
影响因子：
11.1
作者：
Gujral, Taranjit Singh;Peshkin, Leonid;Kirschner, Marc W.
通讯作者：
Kirschner, Marc W.
DOI：
10.1016/0035-9203(56)90036-0
发表时间：
1956-01-01
期刊：
TRANS ROY SOC TROP MED AND HYG
影响因子：
--
作者：
RODHAIN, J.
通讯作者：
RODHAIN, J.