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Tick-borne encephalitis virus induces chemokine RANTES expression via activation of IRF-3 pathway.

Authors :
Xiaowei Zhang
Zhenhua Zheng
Xijuan Liu
Bo Shu
Panyong Mao
Bingke Bai
Qinxue Hu
Minhua Luo
Xiaohe Ma
Zongqiang Cui
Hanzhong Wang
Zhang, Xiaowei
Zheng, Zhenhua
Liu, Xijuan
Shu, Bo
Mao, Panyong
Bai, Bingke
Hu, Qinxue
Luo, Minhua
Ma, Xiaohe
Source :
Journal of Neuroinflammation. 8/30/2016, Vol. 13, p1-18. 18p.
Publication Year :
2016

Abstract

<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
17422094
Volume :
13
Database :
Academic Search Index
Journal :
Journal of Neuroinflammation
Publication Type :
Academic Journal
Accession number :
117796838
Full Text :
https://doi.org/10.1186/s12974-016-0665-9