Rift valley fever virus lacking the NSs and NSm genes is highly attenuated, confers protective immunity from virulent virus challenge, and allows for differential identification of infected and vaccinated animals
Rift valley fever virus lacking the NSs and NSm genes is highly attenuated, confers protective immunity from virulent virus challenge, and allows for differential identification of infected and vaccinated animals
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DOI：
10.1128/jvi.02501-07
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发表时间：
2008-03-01
影响因子：
5.4
通讯作者：
Nichol, Stuart T.
中科院分区：
文献类型：
--
作者：
Bird, Brian H.;Albarino, Cesar G.;Nichol, Stuart T.
裂谷热病毒是一种蚊媒人类和兽医病原体，与整个非洲以及最近阿拉伯半岛大规模暴发的严重疾病有关。牲畜感染可导致大范围的“流产风暴”和幼畜的高死亡率。人类感染导致自限性发热性疾病，大约1 - 2%的患者进展为更严重的并发症，包括肝炎、脑炎和视网膜炎或高致死率的出血性综合征。病毒S片段编码的NSs和M片段编码的NSm蛋白是重要的毒力因子。开发安全、有效的疫苗和工具来筛选和评估抗病毒化合物对未来的控制策略至关重要。在这里，我们报告了成功的反向遗传学一代的多个重组增强绿色荧光蛋白标记的裂谷热病毒含有全长，完整的病毒基因组或精确删除的NS基因单独或NS/NSm基因的组合，从而创建多个病毒基因组片段的减毒删除。这些病毒是高度减毒的，在大鼠致死性疾病模型中使用高攻毒剂量（1.0 × 10（4）PFU）时未观察到可检测的病毒血症或临床疾病。接种后第26天，单剂免疫接种方案诱导产生了强有力的抗裂谷热病毒免疫球蛋白G抗体（滴度类似于1：6，400）。随后用高剂量强毒裂谷热病毒攻击的所有接种疫苗的动物在感染后均存活，并且可以通过缺乏NS抗体在血清学上与未经实验感染的动物区分开来。这些合理设计的裂谷热标记疫苗病毒将是体外筛选治疗性化合物的有用工具，并将为进一步开发裂谷热病毒标记疫苗提供基础，供流行地区使用或在病毒自然或有意引入以前未受影响的地区之后使用。
Rift Valley fever (RVF) virus is a mosquito-borne human and veterinary pathogen associated with large outbreaks of severe disease throughout Africa and more recently the Arabian peninsula. Infection of livestock can result in sweeping "abortion storms" and high mortality among young animals. Human infection results in self-limiting febrile disease that in similar to 1 to 2% of patients progresses to more serious complications including hepatitis, encephalitis, and retinitis or a hemorrhagic syndrome with high fatality. The virus S segment-encoded NSs and the M segment-encoded NSm proteins are important virulence factors. The development of safe, effective vaccines and tools to screen and evaluate antiviral compounds is critical for future control strategies. Here, we report the successful reverse genetics generation of multiple recombinant enhanced green fluorescent protein-tagged RVF viruses containing either the full-length, complete virus genome or precise deletions of the NSs gene alone or the NSs/NSm genes in combination, thus creating attenuating deletions on multiple virus genome segments. These viruses were highly attenuated, with no detectable viremia or clinical illness observed with high challenge dosages (1.0 X 10(4) PFU) in the rat lethal disease model. A single-dose immunization regimen induced robust anti-RVF virus immunoglobulin G antibodies (titer, similar to 1:6,400) by day 26 postvaccination. All vaccinated animals that were subsequently challenged with a high dose of virulent RVF virus survived infection and could be serologically differentiated from naive, experimentally infected animals by the lack of NSs antibodies. These rationally designed marker RVF vaccine viruses will be useful tools for in vitro screening of therapeutic compounds and will provide a basis for further development of RVF virus marker vaccines for use in endemic regions or following the natural or intentional introduction of the virus into previously unaffected areas.