Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany.
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Medical School Hannover, 30625 Hannover, Germany.
Immunity. 2016 Apr 19;44(4):901-12. doi: 10.1016/j.immuni.2016.04.005.
Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.
在患有恶性肿瘤并接受 I 型干扰素 (IFN) 治疗的病毒感染个体以及自身免疫性疾病患者中，疾病行为和认知功能障碍常通过未知机制发生。我们发现，在疾病行为过程中，单链 RNA 病毒、双链 RNA 配体和 IFN 通过黑色素瘤分化相关蛋白 5 (MDA5)、视黄酸诱导基因 1 (RIG-I) 和线粒体抗病毒信号蛋白 (MAVS) 途径发挥作用，随后特异性诱导小鼠脑内皮细胞和上皮细胞的 IFN 反应。行为改变特异性地依赖于脑内皮细胞和上皮细胞 IFN 受体链 1 (IFNAR)。通过基因谱分析，我们发现内皮细胞衍生趋化因子配体 CXCL10 通过损害突触可塑性来介导行为改变。这些结果确定了脑内皮细胞和上皮细胞作为病毒诱导疾病行为的天然守门员，证明了组织特异性 IFNAR 参与，并确定了 CXCL10-CXCR3 轴作为病毒感染和 I 型 IFN 治疗期间治疗行为改变的靶点。
