Abstract
BackgroundTick-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.MethodsBALB/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.ResultsIn 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0665-9) contains supplementary material, which is available to authorized users.
Highlights
Tick-borne encephalitis virus (TBEV) is one of the most important flaviviruses that targets the central nervous system (CNS) and causes encephalitides in humans
We revealed in this study that TBEV-induced transcription of RANTES is mainly mediated by activation of the interferon regulatory factor 3 (IRF-3) pathway
We showed that Retinoic acid-inducible gene 1 (RIG-I)/melanoma differentiation-associated protein 5 (MDA5)- and TANK-binding kinase 1 (TBK1)-directed IRF-3 phosphorylation is critical for TBEV-induced RANTES expression
Summary
Tick-borne encephalitis virus (TBEV) is one of the most important flaviviruses that targets the central nervous system (CNS) and causes encephalitides in humans. Tick-borne encephalitis (TBE), an endemic in many regions of Europe and Asia, is an important emerging infectious disease that targets the central nervous system (CNS) caused by the TBE virus (TBEV; family Flaviviridae, genus Flavivirus). TBEV causes a variety of clinical manifestations, ranging from flu-like febrile disease to encephalitis of differing severity levels [2]. The clinical outcome may in part depend upon the subtype of TBEV infection. Infection with the TBEV-FE subtype results in the most severe CNS disorder, with mortality rates of up to 40 % and higher rates of severe neurologic sequelae [3, 4]
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