Ikegami Tetsuro, Narayanan Krishna, Won Sungyong, Kamitani Wataru, Peters C J, Makino Shinji
Department of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, Galveston, TX, USA.
PLoS Pathog. 2009 Feb;5(2):e1000287. doi: 10.1371/journal.ppat.1000287. Epub 2009 Feb 6.
Rift Valley fever virus (RVFV) (genus Phlebovirus, family Bunyaviridae) is a negative-stranded RNA virus with a tripartite genome. RVFV is transmitted by mosquitoes and causes fever and severe hemorrhagic illness among humans, and fever and high rates of abortions in livestock. A nonstructural RVFV NSs protein inhibits the transcription of host mRNAs, including interferon-beta mRNA, and is a major virulence factor. The present study explored a novel function of the RVFV NSs protein by testing the replication of RVFV lacking the NSs gene in the presence of actinomycin D (ActD) or alpha-amanitin, both of which served as a surrogate of the host mRNA synthesis suppression function of the NSs. In the presence of the host-transcriptional inhibitors, the replication of RVFV lacking the NSs protein, but not that carrying NSs, induced double-stranded RNA-dependent protein kinase (PKR)-mediated eukaryotic initiation factor (eIF)2alpha phosphorylation, leading to the suppression of host and viral protein translation. RVFV NSs promoted post-transcriptional downregulation of PKR early in the course of the infection and suppressed the phosphorylated eIF2alpha accumulation. These data suggested that a combination of RVFV replication and NSs-induced host transcriptional suppression induces PKR-mediated eIF2alpha phosphorylation, while the NSs facilitates efficient viral translation by downregulating PKR and inhibiting PKR-mediated eIF2alpha phosphorylation. Thus, the two distinct functions of the NSs, i.e., the suppression of host transcription, including that of type I interferon mRNAs, and the downregulation of PKR, work together to prevent host innate antiviral functions, allowing efficient replication and survival of RVFV in infected mammalian hosts.
裂谷热病毒（RVFV）（白蛉病毒属，布尼亚病毒科）是一种具有三分体基因组的负链RNA病毒。RVFV通过蚊子传播，可导致人类发热和严重出血性疾病，以及家畜发热和高流产率。RVFV的一种非结构蛋白NSs可抑制宿主mRNA的转录，包括干扰素-β mRNA，是一种主要的毒力因子。本研究通过检测在放线菌素D（ActD）或α-鹅膏蕈碱存在的情况下缺乏NSs基因的RVFV的复制情况，探索了RVFV NSs蛋白的一种新功能，这两种物质均作为NSs宿主mRNA合成抑制功能的替代物。在宿主转录抑制剂存在的情况下，缺乏NSs蛋白的RVFV的复制，而非携带NSs的RVFV的复制，诱导双链RNA依赖性蛋白激酶（PKR）介导的真核起始因子（eIF）2α磷酸化，导致宿主和病毒蛋白翻译受到抑制。RVFV NSs在感染过程早期促进PKR的转录后下调，并抑制磷酸化eIF2α的积累。这些数据表明，RVFV复制和NSs诱导的宿主转录抑制共同诱导PKR介导的eIF2α磷酸化，而NSs通过下调PKR和抑制PKR介导的eIF2α磷酸化促进有效的病毒翻译。因此，NSs的两种不同功能，即抑制宿主转录，包括I型干扰素mRNA的转录，以及下调PKR，共同作用以阻止宿主的先天性抗病毒功能，使RVFV在受感染的哺乳动物宿主中有效复制和存活。
