title: Tick-borne encephalitis virus induces chemokine RANTES expression via activation of IRF-3 pathway.
abstract: Tick-borne encephalitis virus (TBEV) is one of the most important flaviviruses that targets the central nervous system (CNS) and causes encephalitides in humans. Although neuroinflammatory mechanisms may contribute to brain tissue destruction, the induction pathways and potential roles of specific chemokines in TBEV-mediated neurological disease are poorly understood.
  
  
  
  BALB/c mice were intracerebrally injected with TBEV, followed by evaluation of chemokine and cytokine profiles using protein array analysis. The virus-infected mice were treated with the CC chemokine antagonist Met-RANTES or anti-RANTES mAb to determine the role of RANTES in affecting TBEV-induced neurological disease. The underlying signaling mechanisms were delineated using RANTES promoter luciferase reporter assay, siRNA-mediated knockdown, and pharmacological inhibitors in human brain-derived cell culture models.
  
  
  
  In a mouse model, pathological features including marked inflammatory cell infiltrates were observed in brain sections, which correlated with a robust up-regulation of RANTES within the brain but not in peripheral tissues and sera. Antagonizing RANTES within CNS extended the survival of mice and reduced accumulation of infiltrating cells in the brain after TBEV infection. Through in vitro studies, we show that virus infection up-regulated RANTES production at both mRNA and protein levels in human brain-derived cell lines and primary progenitor-derived astrocytes. Furthermore, IRF-3 pathway appeared to be essential for TBEV-induced RANTES production. Site mutation of an IRF-3-binding motif abrogated the RANTES promoter activity in virus-infected brain cells. Moreover, IRF-3 was activated upon TBEV infection as evidenced by phosphorylation of TBK1 and IRF-3, while blockade of IRF-3 activation drastically reduced virus-induced RANTES expression.
  
  
  
  Our findings together provide insights into the molecular mechanism underlying RANTES production induced by TBEV, highlighting its potential importance in the process of neuroinflammatory responses to TBEV infection.
authors: Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Xiaohongshan No.44, Wuhan, 430071, China.|State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Xiaohongshan No.44, Wuhan, 430071, China.
authors: Xiaowei
authors: X
authors: Zhang
authors: Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Xiaohongshan No.44, Wuhan, 430071, China.|State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Xiaohongshan No.44, Wuhan, 430071, China.
authors: Zhenhua
authors: Z
authors: Zheng
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Xiaohongshan No.44, Wuhan, 430071, China.
authors: Xijuan
authors: X
authors: Liu
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Xiaohongshan No.44, Wuhan, 430071, China.
authors: Bo
authors: B
authors: Shu
authors: Beijing 302 Hospital, Beijing, 100039, China.
authors: Panyong
authors: P
authors: Mao
authors: Beijing 302 Hospital, Beijing, 100039, China.
authors: Bingke
authors: B
authors: Bai
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Xiaohongshan No.44, Wuhan, 430071, China.
authors: Qinxue
authors: Q
authors: Hu
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Xiaohongshan No.44, Wuhan, 430071, China.|CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Shanghai, China.
authors: Minhua
authors: M
authors: Luo
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Xiaohongshan No.44, Wuhan, 430071, China.
authors: Xiaohe
authors: X
authors: Ma
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Xiaohongshan No.44, Wuhan, 430071, China. czq@wh.iov.cn.
authors: Zongqiang
authors: Z
authors: Cui
authors: Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Xiaohongshan No.44, Wuhan, 430071, China. wanghz@wh.iov.cn.|State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Xiaohongshan No.44, Wuhan, 430071, China. wanghz@wh.iov.cn.
authors: Hanzhong
authors: H
authors: Wang
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000235:genetics; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D004669:Encephalitis Viruses, Tick-Borne / Q000235:genetics / Q000378:metabolism*; D004675:Encephalitis, Tick-Borne / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000502:physiology*; D019562:Viral Load / Q000639:trends
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D018925:Chemokines; D050838:Interferon Regulatory Factor-3
keywords: Chemokine; IRF-3; Neuroinflammation; RANTES; Tick-borne encephalitis virus