Division of Virology, Defence Research & Development Establishment, Gwalior 474002, India.
School of Studies in Neurosciences, Jiwaji University, Gwalior 474002, India.
Virus Res. 2014 Aug 30;189:194-205. doi: 10.1016/j.virusres.2014.05.010. Epub 2014 Jun 4.
Chikungunya virus (CHIKV) has received global attention due to the series of large-scale outbreaks in different parts of the world. Many unusual clinical severities including neurological complications and death were reported in recent outbreaks. The mechanism underlying the host immune response to CHIKV in the brain is poorly characterized. In this study, the neuropathogenesis of CHIKV with E1:A226V mutation was elucidated in 1 week old BALB/c mice. The virus was found to replicate in mice brain with peak titer of 10(4) on 6th day post infection. Immunohistochemical analysis revealed preferential virus localization in neuronal cells of cerebellum. The expression profiling of TLR, antiviral genes and cytokines in mice brain revealed significant up regulation of TLR3, TRAF-6, TICAM-1, MCP-1, CXCL-10, IL-6, IL-4, ISG-15, MX-2, IFN-β, OAS-3 genes that ultimately resulted in virus clearance from brain by day 9-10 suggesting activation of innate immune pathway. Further the effect of poly I: C (Polyinosinic: Polycytidylic acid), a TLR-3 agonist and potent IFN inducer on CHIKV neuropathogenesis was studied. Pretreatment of mice with Poly I: C caused reduction of CHIKV titer in brain and offered 100% protection of animals. The protection was mediated by an increased induction of TLR3, IFN-β and antiviral genes in mice brain. Our result demonstrates that pre immune stimulation of animals by Poly I: C is effective inhibitor of CHIKV replication and might be a promising prevention agent against this virus.
基孔肯雅病毒（CHIKV）在世界不同地区爆发了一系列大规模疫情，因此受到了全球关注。最近的疫情报告了许多不寻常的临床严重程度，包括神经并发症和死亡。宿主对 CHIKV 在大脑中的免疫反应的机制尚未得到很好的描述。在这项研究中，阐明了具有 E1:A226V 突变的 CHIKV 在 1 周龄 BALB/c 小鼠中的神经发病机制。该病毒在感染后第 6 天在小鼠脑中复制，滴度峰值为 10(4)。免疫组织化学分析显示病毒优先定位于小脑神经元细胞中。对小鼠大脑中 TLR、抗病毒基因和细胞因子的表达谱分析显示，TLR3、TRAF-6、TICAM-1、MCP-1、CXCL-10、IL-6、IL-4、ISG-15、MX-2、IFN-β、OAS-3 基因的表达显著上调，这些基因最终导致病毒在第 9-10 天从大脑中清除，提示先天免疫途径的激活。进一步研究了 TLR-3 激动剂和强效 IFN 诱导剂 Poly I:C（聚肌苷酸：聚胞苷酸）对 CHIKV 神经发病机制的影响。用 Poly I:C 预处理小鼠可降低脑中的 CHIKV 滴度，并为 100%的动物提供保护。这种保护是通过增加小鼠大脑中 TLR3、IFN-β 和抗病毒基因的诱导来介导的。我们的结果表明，用 Poly I:C 对动物进行免疫前刺激是 CHIKV 复制的有效抑制剂，可能是预防这种病毒的有前途的药物。
