Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.
Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
mSphere. 2020 Jul 1;5(4):e00377-20. doi: 10.1128/mSphere.00377-20.
Enterovirus A71 (EV-A71) is the major pathogen of hand, foot, and mouth disease (HFMD); in some severe cases, it could develop into central nervous system (CNS) disease such as aseptic meningitis, encephalitis, and neurogenic pulmonary edema in children under 5 years. The EV-A71 pathogenesis which is involved with the CNS is unclear due to the lack of a simple and reliable mouse model thus far. Most clinical EV-A71 isolates could not effectively infect the neonatal mouse, which used to be an EV-A71 infection model. The small extracellular vesicles (sEVs) released from clinical EV-A71 isolate-infected cells were infectious in cell lines and could cause a high viral replication in mice. Neonatal ICR mice were injected intraperitoneally with these infectious sEVs and showed more weight loss and higher mortality than those mice injected with the clinical EV-A71 isolate. By using these sEVs, we provided a simple and effective method by which we can generate a stable and valuable animal model for the studies of EV-A71 pathogenesis and therapy. EV-A71 was supposed to infect the CNS through the neural pathway and the circulation of the blood in previous studies. Reverse axon transport had been confirmed as an important pathway for EV-A71 to infect the CNS; however, it is still unknown how EV-A71 infects the CNS through the circulation of the blood. Combined with the infectivity of sEVs secreted from EV-A71-infected cells and the characteristic that sEVs could cross the blood-brain barrier, we considered that sEVs may play a vital role in EV-A71 pathogenesis of the CNS.
肠道病毒 A71（EV-A71）是手足口病（HFMD）的主要病原体；在一些严重的情况下，它可能会发展为 5 岁以下儿童的中枢神经系统（CNS）疾病，如无菌性脑膜炎、脑炎和神经性肺水肿。由于缺乏简单可靠的小鼠模型，目前尚不清楚与中枢神经系统有关的 EV-A71 发病机制。大多数临床 EV-A71 分离株不能有效地感染新生小鼠，而新生小鼠曾是 EV-A71 感染模型。从临床 EV-A71 分离株感染细胞释放的小细胞外囊泡（sEVs）在细胞系中具有感染性，并可导致小鼠中高病毒复制。新生 ICR 小鼠经腹腔注射这些感染性 sEVs 后，体重减轻和死亡率均高于注射临床 EV-A71 分离株的小鼠。通过使用这些 sEVs，我们提供了一种简单有效的方法，可以为 EV-A71 发病机制和治疗的研究生成一个稳定且有价值的动物模型。在以前的研究中，EV-A71 被认为通过神经途径和血液循环感染中枢神经系统。反向轴突运输已被证实是 EV-A71 感染中枢神经系统的重要途径；然而，EV-A71 如何通过血液循环感染中枢神经系统仍不清楚。结合 EV-A71 感染细胞分泌的 sEVs 的感染性和 sEVs 可以穿过血脑屏障的特性，我们认为 sEVs 可能在 EV-A71 对中枢神经系统的发病机制中发挥重要作用。
