Intranasal herpes simplex virus type 2 inoculation causes a profound thymidine kinase dependent cerebral inflammatory response in the mouse hindbrain
Intranasal herpes simplex virus type 2 inoculation causes a profound thymidine kinase dependent cerebral inflammatory response in the mouse hindbrain
复制标题
DOI：
10.1046/j.1460-9568.2002.02057.x
复制
发表时间：
2002-07-01
影响因子：
3.4
通讯作者：
Rivest, S
中科院分区：
文献类型：
--
作者：
Boivin, G;Coulombe, Z;Rivest, S
单纯疱疹病毒（HSV）具有在中枢神经系统（CNS）中复制的能力，这可能导致致命的脑炎。本研究探讨了核因子κ B（NF-κ B）的活性和细胞因子/趋化因子基因在HSV感染小鼠脑中的表达模式，以及病毒胸苷激酶（TK）在介导这些效应中的作用。鼻内接种HSV-2 TK活性或TK缺陷临床分离株后1-8天处死小鼠。TK-感受态病毒感染的动物在接种后第5天表现出首次感染体征，而在第6天和第8天之间观察到严重的疾病体征。在这些动物的脑中，在脑桥和延髓的许多区域中发现了编码抑制因子κ B α（IkappaB α，NF-κ B活性指数）、Toll样受体2（TLR 2）、肿瘤坏死因子α（TNF-α）和单核细胞趋化蛋白-1（MCP-1）的基因的强大杂交信号。这些基因的表达水平在接种后4天增加，并在第6天在脑毛细血管内皮和髓样起源细胞内达到峰值。在表现出免疫分子表达的区域内选择性地检测到TK基因及其编码蛋白的稳健信号。相比之下，接受TK缺陷病毒的动物没有显示出任何疾病或脑炎症或脑组织内HSV复制的迹象。目前的数据提供了明确的证据表明，HSV-2有能力在神经元中以病毒TK依赖性HSV复制的模式触发深刻的炎症反应。这种发生在后脑的神经毒力在这里提出直接负责神经变性，并导致大脑先天免疫反应，这反过来又可能在致命的HSV-2诱导的脑炎中发挥关键作用。
The herpes simplex virus (HSV) has the ability to replicate in the central nervous system (CNS), which may cause fatal encephalitis. The present study investigated the activity of the nuclear factor kappa B (NF-kappaB) and the pattern of cytokine/chemokine gene expression across the brain of HSV-infected mice and the role of the viral thymidine kinase (TK) in mediating these effects. Mice were killed 1-8 days after intranasal inoculation with either HSV-2 TK-competent or TK-deficient clinical isolates. Animals infected with the TK-competent virus exhibited first signs of infection at day 5 postinoculation, whereas severe signs of sickness were observed between day 6 and 8. A robust hybridization signal was found in the brain of these animals for the gene encoding the inhibitory factor kappaBalpha (IkappaBalpha, index of NF-kappaB activity), toll-like receptor 2 (TLR2), tumour necrosis factor alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1) in numerous regions of the pons and medulla. The levels of expression of these genes increased 4 days after the inoculation and peaked at day 6 within the endothelium of the brain capillaries and cells of myeloid origin. A robust signal for the TK gene and its encoding protein was detected selectively within the regions that exhibited expression of the immune molecules. In contrast, animals that received the TK-deficient virus did not show any signs of sickness or cerebral inflammation or HSV replication within the cerebral tissue. The present data provide clear evidence that HSV-2 has the ability to trigger a profound inflammatory response in a pattern that follows the viral TK-dependent HSV replication in neurons. Such neurovirulence occurring in the hindbrain is proposed here to be directly responsible for neurodegeneration and to lead to the cerebral innate immune response, which in turn could play a key role in fatal HSV-2-induced encephalitis.