Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Ave N #500, Seattle, WA, 98109, USA.
Department of Biomedical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
Nat Commun. 2017 Nov 1;8(1):1232. doi: 10.1038/s41467-017-01345-2.
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.
疟原虫在感染的必需肝脏阶段从宿主肝细胞中获得广泛的需求，但对于特定的宿主调节剂知之甚少。在这里，我们评估了 34 种针对宿主的激酶抑制剂，以评估它们消除感染的疟原虫耶氏疟原虫（Plasmodium yoelii）感染肝细胞的能力。利用每种抑制剂现有的活性谱，我们生成了一个预测性的计算模型，该模型可以识别促进疟原虫耶氏疟原虫肝脏阶段感染的宿主激酶。我们预测了 47 种激酶，包括影响感染的新的和以前描述过的激酶。一部分激酶的影响通过实验得到了验证，包括受体酪氨酸激酶、MAP 激酶级联反应的成员和 WEE1。我们的方法还预测了感染的宿主靶向激酶抑制剂，包括已经在人类中使用的化合物。其中三种化合物，VX-680、罗苏伐他汀和舒尼替尼，每种化合物都能消除超过 85%的感染。我们的方法非常适合在困难的模型系统中发现感染的关键宿主决定因素，包括来自野外的寄生虫和/或新兴病原体。
