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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

targeted therapies in conversion therapy in mcrc a systematic review and meta analysis

n/

Model testing on rainfall-induced landslide of loose soil in Wenchuan earthquake region

This study investigates the formation process of rainfall-induced landslide for slopes composed of loose soil in the Wenchuan earthquake region. Experimental investigations have been performed on the landslide's formation and the variation of the controlling soil parameters under various artificial rainfall conditions. The landslide triggering mechanisms can be described in the following way. Firstly, the large porosity of the loose soil facilitated the infiltration of water, which increased the pore water pressure and reduced the shear strength of the soil significantly. In addition, the rainfalls probably caused the concentration of finer particles at a certain depth of the valley slopes. This concentration within the soil increased the pore water pressure significantly, and consequently reduced both the porosity ratio and permeability. Therefore, when the pore water pressure reached a critical state, the effective shear strength of the soil diminished, inducing the landslide's formation