RNA病毒逃逸宿主免疫因子Tetherin/BST-2限制的分子机制

狂犬病病毒（RABV）侵入中枢神经后呈指数式增殖且不引起免疫反应，导致宿主病死率为100%，其病理机制至今仍不清楚。BST-2是宿主限制囊膜病毒释放、增殖和传播的重要免疫因子，并参与调控先天性免疫和适应性免疫反应。我们前期研究发现，RABV感染小鼠模型后脑组织中BST-2的mRNA水平上调高达50倍，且BST-2与RABV呈强烈细胞膜共定位，过表达BST-2能极显著抑制RABV的增殖，这提示BST-2在RABV增殖和致病中发挥关键作用。因此，本项目拟以神经细胞作为体外模型，以BST-2基因缺失小鼠为体内模型，探索BST-2对RABV释放的限制作用，分析这种限制对RABV激活先天性免疫和适应性免疫的影响，并利用反向遗传系统构建靶点突变型RABV，定位RABV结构蛋白与BST-2互作的关键靶点，阐明BST-2在RABV免疫逃逸中的作用机制，为进一步揭示狂犬病病毒的致病机制奠定基础。

Rabies virus (RABV) invades the central nerve system with exponential multiplications but little immune responses, causing 100% death rate. However, the pathological mechanisms remain unclear so far. The host immune factor BST-2 restricts the releases, multiplies and spreads of the enveloped viruses, and is involved in regulating the innate and adaptive immune responses. Our previous studies have demonstrated the mRNA levels of BST-2 up-regulates almost 50 times in brains of RABV-infected mice, and in vitro, propagations of RABV are closely related to the expressions of BST-2 with significantly membrane localizations. In addition, the viral propagations in BST-2 overexpressed BSR are remarkably inhibited. These findings suggest that the BST-2 plays critical roles in propagation and pathogenicity of RABV. Thus, in the present study, we intend to investigate the restrictions of BST-2 on the releases of RABV, analyze the effects of this restriction on RABV activations of innate and adaptive immunity, find out the key targets of viral proteins interacted with BST-2 and verify with the BST-2-blind RABV generated by reverse genetics in nerve cells and in BST-2 gene deleted mice. We aim to elucidate the molecular mechanism of BST-2 in the course of immune escape of RABV for furtherly revealing the pathogenic mechanism of RABV.