Replication and clearance of Venezuelan equine encephalitis virus from the brains of animals vaccinated with chimeric SIN/VEE viruses
Replication and clearance of Venezuelan equine encephalitis virus from the brains of animals vaccinated with chimeric SIN/VEE viruses
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DOI：
10.1128/jvi.80.6.2784-2796.2006
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发表时间：
2006-03-01
影响因子：
5.4
通讯作者：
Frolov, I
中科院分区：
文献类型：
--
作者：
Paessler, S;Ni, HL;Frolov, I
委内瑞拉马脑炎病毒（Venezuelanequineencephalitis virus，VFEV）是一种重要的自然新发人畜共患病原体。最近于1995年在委内瑞拉和哥伦比亚爆发的VEEV，估计涉及100，000例人间病例，表明VEEV仍然构成严重的公共卫生威胁。为了开发一种安全、有效的疫苗，以防止由VEEV感染引起的疾病，我们产生了嵌合辛德毕斯（SIN）病毒表达不同株的VEEV的结构蛋白，并分析了它们在体外和体内的复制，以及诱导的免疫应答的特征。在脑内（i.c.）或皮下（s.c.）在i.c.接种后，所有嵌合体在6日龄小鼠中比疫苗株VEEV TC 83更减毒。感染所有接种疫苗的小鼠在i.c.，s.c.，或鼻内（i.n.）用强毒VEEV ZPC 738株（ZPC 738）攻毒。尽管在通过i.n.或I.C.通过这一途径，我们定期在中枢神经系统（CNS）中检测到高水平的感染性攻毒病毒。然而，在攻击后28天，在所有免疫动物的脑中均未检测到感染性病毒。用嵌合SIN/VEE病毒接种的仓鼠也保护免于s.c.挑战ZPC 738综上所述，我们的研究结果表明，这些嵌合SIN/VEE病毒在成年小鼠和仓鼠中是安全有效的，并且可能用作VEEV疫苗。此外，免疫动物为研究抗VEEV神经炎症反应的机制提供了有用的模型，导致CNS中病毒滴度的降低和动物的存活。
Venezuelan equine encephalitis virus (VFEV) is an important, naturally emerging zoonotic pathogen. Recent outbreaks in Venezuela and Colombia in 1995, involving an estimated 100,000 human cases, indicate that VEEV still poses a serious public health threat. To develop a safe, efficient vaccine that protects against disease resulting from VEEV infection, we generated chimeric Sindbis (SIN) viruses expressing structural proteins of different strains of VEEV and analyzed their replication in vitro and in vivo, as well as the characteristics of the induced immune responses. None of the chimeric SIN/VEE viruses caused any detectable disease in adult mice after either intracerebral (i.c.) or subcutaneous (s.c.) inoculation, and all chimeras were more attenuated than the vaccine strain, VEEV TC83, in 6-day-old mice after i.c. infection. All vaccinated mice were protected against lethal encephalitis following i.c., s.c., or intranasal (i.n.) challenge with the virulent VEEV ZPC738 strain (ZPC738). In spite of the absence of clinical encephalitis in vaccinated mice challenged with ZPC738 via i.n. or i.c. route, we regularly detected high levels of infectious challenge virus in the central nervous system (CNS). However, infectious virus was undetectable in the brains of all immunized animals at 28 days after challenge. Hamsters vaccinated with chimeric SIN/VEE viruses were also protected against s.c. challenge with ZPC738. Taken together, our findings suggest that these chimeric SIN/VEE viruses are safe and efficacious in adult mice and hamsters and are potentially useful as VEEV vaccines. In addition, immunized animals provide a useful model for studying the mechanisms of the anti-VEEV neuroinflammatory response, leading to the reduction of viral titers in the CNS and survival of animals.