Pathogenesis Study of Enterovirus 71 Using a Novel Human SCARB2 Knock-In Mouse Model.
Pathogenesis Study of Enterovirus 71 Using a Novel Human SCARB2 Knock-In Mouse Model.
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DOI：
10.1128/msphere.01048-20
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发表时间：
2021-03-10
期刊：
影响因子：
4.8
通讯作者：
Duan G
中科院分区：
文献类型：
--
作者：
Jin Y;Sun T;Zhou G;Li D;Chen S;Zhang W;Li X;Zhang R;Yang H;Duan G
肠病毒71型（EV71）可引起严重的儿童手足口病。然而，由于没有合适的动物模型，ev71相关疾病的确切机制，特别是神经发病机制和肺部疾病，仍未完全了解。人类清道夫受体B类成员2 （hSCARB2）是EV71的细胞受体。在此，我们利用CRISPR/Cas9系统建立了一种新的敲入（KI）小鼠模型，将hSCARB2基因插入小鼠Rosa26位点，以研究EV71的发病机制。感染EV71临床分离株的hSCARB2 KI小鼠出现神经系统症状，如共济失调、瘫痪和死亡。病毒复制主要在星形胶质细胞和有限数量的神经元和小胶质细胞中检测到，并伴有胶质细胞增生。检测到血管渗漏和肺泡充满红细胞，提示ev71感染的KI小鼠也发生了人类患者观察到的水肿和出血。此外，感染KI小鼠血清中促炎因子和趋化因子显著升高。KI小鼠感染后的这些病理特征与人EV71型脑脊髓炎相似。因此，我们的KI小鼠模型适合研究EV71的发病机制，对开发治疗或预防EV71感染的抗病毒药物和疫苗具有重要意义。肠病毒71 （EV71）与严重手足口病有关。近年来，亚太地区报告了EV71型感染疫情，死亡率高，对全球公共卫生构成了巨大挑战。迄今为止，由于没有合适的动物模型，ev71诱导疾病的确切机制，特别是神经发病机制和呼吸系统疾病，仍未完全了解。人类清道夫受体B类成员2 （hSCARB2）已被确定为EV71的细胞受体。在此，我们引入一种新的CRISPR/ cas9介导的hSCARB2敲入（KI）小鼠模型来研究EV71的发病机制，这对开发抗病毒药物和疫苗具有重要意义。
Enterovirus 71 (EV71) can cause a severe hand-foot-mouth disease in children. However, the precise mechanism of EV71-associated disease, particularly the neuropathogenesis and pulmonary disorder, is still not fully understood because no suitable animal models are available. The human scavenger receptor class B, member 2 (hSCARB2), is a cellular receptor for EV71. Here, we generated a novel knock-in (KI) mouse model using the CRISPR/Cas9 system to insert the hSCARB2 gene into the mouse Rosa26 locus to study the pathogenesis of EV71. The hSCARB2 KI mice infected with clinical isolates of EV71 showed neurological symptoms, such as ataxia, paralysis, and death. Viral replication was detected in mainly astrocytes and a limited number of neurons and microglia, accompanied by gliosis. Vascular leakage and alveoli filled with erythrocytes were detected, suggesting that edema and hemorrhage, which are observed in human patients, also occurred in EV71-infected KI mice. In addition, proinflammatory cytokines and chemokines were significantly increased in the serum of infected KI mice. These pathological features of the KI mice after infection resembled those of EV71 encephalomyelitis in humans. Therefore, our KI mouse model is suitable to study the pathogenesis of EV71 and is of great significance for development of antiviral drugs and vaccines to treat or prevent EV71 infection. IMPORTANCE Enterovirus 71 (EV71) is associated with severe hand-foot-mouth disease. Recently, outbreaks of EV71 infection with high mortality have been reported in the Asia-Pacific region, posing a great challenge for global public health. To date, the precise mechanism of EV71-induced disease, particularly the neuropathogenesis and respiratory disorders, is still not fully understood because no suitable animal models are available. Human scavenger receptor class B, member 2 (hSCARB2), has been identified as a cellular receptor for EV71. Here, we introduce a novel CRISPR/Cas9-mediated hSCARB2 knock-in (KI) mouse model for the study of EV71 pathogenesis, which is of great significance for the development of antiviral drugs and vaccines.