Tian Bin, Zhou Ming, Yang Yu, Yu Lan, Luo Zhaochen, Tian Dayong, Wang Ke, Cui Min, Chen Huanchun, Fu Zhen F, Zhao Ling
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.
Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan, China.
Front Immunol. 2018 Jan 19;8:2011. doi: 10.3389/fimmu.2017.02011. eCollection 2017.
Rabies is an ancient disease but remains endemic in most parts of the world and causes approximately 59,000 deaths annually. The mechanism through which the causative agent, rabies virus (RABV), evades the host immune response and infects the host central nervous system (CNS) has not been completely elucidated thus far. Our previous studies have shown that lab-attenuated, but not wild-type (wt), RABV activates the innate immune response in the mouse and dog models. In this present study, we demonstrate that lab-attenuated RABV causes abortive infection in astrocytes, the most abundant glial cells in the CNS. Furthermore, we found that lab-attenuated RABV produces more double-stranded RNA (dsRNA) than wt RABV, which is recognized by retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated protein 5 (MDA5). Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. Notably, lab-attenuated RABV replicates in a manner identical to that of wt RABV in MAVS-/- astrocytes. It was also found that lab-attenuated, but not wt, RABV induces the expression of inflammatory cytokines the MAVS- p38/NF-κB signaling pathway. These inflammatory cytokines increase the blood-brain barrier permeability and thus enable immune cells and antibodies infiltrate the CNS parenchyma, resulting in RABV control and elimination. In contrast, wt RABV restricts dsRNA production and thus evades innate recognition by RIG-I/MDA5 in astrocytes, which could be one of the mechanisms by which wt RABV evades the host immune response in resident CNS cells. Our findings suggest that astrocytes play a critical role in limiting the replication of lab-attenuated RABV in the CNS.
狂犬病是一种古老的疾病，但在世界大部分地区仍然流行，每年导致约59000人死亡。迄今为止，致病因子狂犬病病毒（RABV）逃避宿主免疫反应并感染宿主中枢神经系统（CNS）的机制尚未完全阐明。我们之前的研究表明，实验室减毒的RABV（而非野生型RABV）在小鼠和犬模型中激活先天免疫反应。在本研究中，我们证明实验室减毒的RABV在星形胶质细胞（CNS中最丰富的神经胶质细胞）中引起流产性感染。此外，我们发现实验室减毒的RABV比野生型RABV产生更多的双链RNA（dsRNA），其可被视黄酸诱导基因I（RIG-I）或黑色素瘤分化相关蛋白5（MDA5）识别。线粒体抗病毒信号蛋白（MAVS）作为RIG-I和MDA5的共同衔接分子，其激活会导致I型干扰素（IFN）的产生以及数百种IFN刺激基因的表达，从而抑制RABV在星形胶质细胞中的复制和传播。值得注意的是，实验室减毒的RABV在MAVS基因敲除的星形胶质细胞中的复制方式与野生型RABV相同。还发现实验室减毒的RABV（而非野生型RABV）通过MAVS-p38/NF-κB信号通路诱导炎性细胞因子的表达。这些炎性细胞因子增加血脑屏障通透性，从而使免疫细胞和抗体浸润CNS实质，导致RABV被控制和清除。相比之下，野生型RABV限制dsRNA的产生，从而逃避星形胶质细胞中RIG-I/MDA5的先天识别，这可能是野生型RABV在驻留CNS细胞中逃避宿主免疫反应的机制之一。我们的研究结果表明，星形胶质细胞在限制实验室减毒的RABV在CNS中的复制方面起着关键作用。
