Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
PLoS One. 2010 Nov 24;5(11):e15483. doi: 10.1371/journal.pone.0015483.
As an arthropod-borne human pathogen, Rift Valley fever virus (RVFV) cycles between an insect vector and mammalian hosts. Little is known about the cellular requirements for infection in either host. Here we developed a tissue culture model for RVFV infection of human and insect cells that is amenable to high-throughput screening. Using this approach we screened a library of 1280 small molecules with pharmacologically defined activities and identified 59 drugs that inhibited RVFV infection with 15 inhibiting RVFV replication in both human and insect cells. Amongst the 15 inhibitors that blocked infection in both hosts was a subset that inhibits protein kinase C. Further studies found that infection is dependent upon the novel protein kinase C isozyme epsilon (PKCε) in both human and insect cells as well as in adult flies. Altogether, these data show that inhibition of cellular factors required for early steps in the infection cycle including PKCε can block RVFV infection, and may represent a starting point for the development of anti-RVFV therapeutics.
裂谷热病毒（RVFV）是一种节肢动物传播的人类病原体，在昆虫媒介和哺乳动物宿主之间循环。人们对这两种宿主中感染的细胞要求知之甚少。在这里，我们开发了一种适用于人类和昆虫细胞 RVFV 感染的组织培养模型，可进行高通量筛选。使用这种方法，我们筛选了一个包含 1280 种具有药理学定义活性的小分子的文库，并鉴定出 59 种抑制 RVFV 感染的药物，其中 15 种抑制 RVFV 在人类和昆虫细胞中的复制。在阻止两种宿主感染的 15 种抑制剂中，有一组抑制剂可抑制蛋白激酶 C。进一步的研究发现，感染依赖于新型蛋白激酶 C 同工酶 ε（PKCε），在人类和昆虫细胞以及成年果蝇中均如此。总之，这些数据表明，抑制感染周期早期所需的细胞因子，包括 PKCε，可阻断 RVFV 感染，这可能是开发抗 RVFV 治疗方法的起点。
