EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production
EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production
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EV71 感染通过激活 TLR7 信号传导和 IL-6 产生诱导神经变性。
DOI：
10.1371/journal.ppat.1008142
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发表时间：
2019-11-01
期刊：
影响因子：
6.7
通讯作者：
Wu, Jianguo
中科院分区：
文献类型：
--
作者：
Luo, Zhen;Su, Rui;Wu, Jianguo
作为一种嗜神经病毒，人类肠病毒71 （EV71）感染可引起手足口病（HFMD），并可能在婴儿中发展严重的神经系统疾病。toll样受体7 （TLR7）是一种先天性免疫受体，也是中枢神经系统（CNS）中的一种死亡受体。然而，tlr7介导的脑发病机制对EV71感染的调控机制在很大程度上仍然是未知的。本研究揭示了EV71在C57BL/6小鼠和人类星形胶质瘤U251细胞中感染脑内星形胶质细胞并通过TLR7和白细胞介素-6 （IL-6）诱导神经发病的新机制。在EV71感染后，野生型（WT）小鼠与TLR7-/-小鼠相比，表现出更明显的体重减轻、更高的临床评分和更低的存活率。在ev71感染小鼠的大脑皮层中，WT小鼠的神经丝完整性被破坏，炎症细胞浸润和神经变性被诱导，而TLR7-/-小鼠基本没有这些。同样，与TLR7-/-小鼠相比，ev71感染的WT小鼠IL-6的产生、Caspase-3的切割和细胞凋亡显著增加。此外，EV71可优先感染和诱导小鼠脑星形胶质细胞中的IL-6。在U251细胞中，通过shrna介导的TLR7 （shTLR7）下调，ev71诱导的IL-6产生和细胞凋亡受到抑制。此外，在ev71感染小鼠的大脑皮层中，用抗IL-6抗体（IL-6- ab）阻断IL-6可以恢复体重减轻，减轻临床评分，提高生存率，减少神经丝完整性的破坏，减少细胞凋亡诱导，降低Caspase-3切割水平。同样，在ev71感染的U251细胞中，IL-6- ab阻断ev71诱导的IL-6产生和细胞凋亡，以响应病毒感染。在ev71感染的人脑中表现出TLR7上调、IL-6诱导和星形细胞凋亡。综上所述，我们提出EV71感染小鼠和人类大脑皮层的星形胶质细胞，触发TLR7信号和IL-6释放，随后诱导大脑神经发病。
As a neurotropic virus, human Enterovirus 71 (EV71) infection causes hand-foot-and-mouth disease (HFMD) and may develop severe neurological disorders in infants. Toll-like receptor 7 (TLR7) acts as an innate immune receptor and is also a death receptor in the central nervous system (CNS). However, the mechanisms underlying the regulation of TLR7-mediated brain pathogenesis upon EV71 infection remain largely elusive. Here we reveal a novel mechanism by which EV71 infects astrocytes in the brain and induces neural pathogenesis via TLR7 and interleukin-6 (IL-6) in C57BL/6 mice and in human astroglioma U251 cells. Upon EV71 infection, wild-type (WT) mice displayed more significant body weight loss, higher clinical scores, and lower survival rates as compared with TLR7-/- mice. In the cerebral cortex of EV71-infected mice, neurofilament integrity was disrupted, and inflammatory cell infiltration and neurodegeneration were induced in WT mice, whereas these were largely absent in TLR7-/- mice. Similarly, IL-6 production, Caspase-3 cleavage, and cell apoptosis were significantly higher in EV71-infected WT mice as compared with TLR7-/- mice. Moreover, EV71 preferentially infected and induced IL-6 in astrocytes of mice brain. In U251 cells, EV71-induced IL-6 production and cell apoptosis were suppressed by shRNA-mediated knockdown of TLR7 (shTLR7). Moreover, in the cerebral cortex of EV71-infected mice, the blockade of IL-6 with anti-IL-6 antibody (IL-6-Ab) restored the body weight loss, attenuated clinical scores, improved survival rates, reduced the disruption of neurofilament integrity, decreased cell apoptotic induction, and lowered levels of Caspase-3 cleavage. Similarly, in EV71-infected U251 cells, IL-6-Ab blocked EV71-induced IL-6 production and cell apoptosis in response to viral infection. Collectively, it’s exhibited TLR7 upregulation, IL-6 induction and astrocytic cell apoptosis in EV71-infected human brain. Taken together, we propose that EV71 infects astrocytes of the cerebral cortex in mice and human and triggers TLR7 signaling and IL-6 release, subsequently inducing neural pathogenesis in the brain.