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Zika virus induces neuronal and vascular degeneration in developing mouse retina
Acta Neuropathologica Communications ( IF 7.1 ) Pub Date : 2021-05-25 , DOI: 10.1186/s40478-021-01195-6
Yi Li 1 , Shuizhen Shi 1 , Fan Xia 1 , Chao Shan 2 , Yonju Ha 1 , Jing Zou 2 , Awadalkareem Adam 3 , Ming Zhang 4 , Tian Wang 3 , Hua Liu 1, 5 , Pei-Yong Shi 2, 6 , Wenbo Zhang 1, 6, 7
Affiliation  

Zika virus (ZIKV), a mosquito-borne flavivirus, can cause severe eye disease and even blindness in newborns. However, ZIKV-induced retinal lesions have not been studied in a comprehensive way, mechanisms of ZIKV-induced retinal abnormalities are unknown, and no therapeutic intervention is available to treat or minimize the degree of vision loss in patients. Here, we developed a novel mouse model of ZIKV infection to evaluate its impact on retinal structure. ZIKV (20 plaque-forming units) was inoculated into neonatal wild type C57BL/6J mice at postnatal day (P) 0 subcutaneously. Retinas of infected mice and age-matched controls were collected at various ages, and retinal structural alterations were analyzed. We found that ZIKV induced progressive neuronal and vascular damage and retinal inflammation starting from P8. ZIKV-infected retina exhibited dramatically decreased thickness with loss of neurons, initial neovascular tufts followed by vessel dilation and degeneration, increased microglia and leukocyte recruitment and activation, degeneration of astrocyte network and gliosis. The above changes may involve inflammation and endoplasmic reticulum stress-mediated cell apoptosis and necroptosis. Moreover, we evaluated the efficacy of preclinical drugs and the safety of ZIKV vaccine candidate in this mouse model. We found that ZIKV-induced retinal abnormalities could be blocked by a selective flavivirus inhibitor NITD008 and a live-attenuated ZIKV vaccine candidate could potentially induce retinal abnormalities. Overall, we established a novel mouse model and provide a direct causative link between ZIKV and retinal lesion in vivo, which warrants further investigation of the underlying mechanisms of ZIKV-induced retinopathy and the development of effective therapeutics.

中文翻译:

寨卡病毒诱导小鼠视网膜发育过程中的神经元和血管变性

寨卡病毒 (ZIKV) 是一种通过蚊子传播的黄病毒,可导致新生儿出现严重的眼病甚至失明。然而,ZIKV 引起的视网膜病变尚未得到全面研究,ZIKV 引起的视网膜异常的机制尚不清楚,也没有治疗干预措施来治疗或尽量减少患者的视力丧失程度。在这里,我们开发了一种新型 ZIKV 感染小鼠模型,以评估其对视网膜结构的影响。ZIKV(20 个斑块形成单位)在出生后第 0 天皮下接种到新生野生型 C57BL/6J 小鼠中。在不同年龄收集受感染小鼠和年龄匹配的对照的视网膜,并分析视网膜结构改变。我们发现 ZIKV 从 P8 开始诱导进行性神经元和血管损伤以及视网膜炎症。ZIKV 感染的视网膜厚度显着减少,神经元丢失,最初的新生血管簇随后血管扩张和退化,小胶质细胞和白细胞募集和激活增加,星形胶质细胞网络退化和神经胶质增生。上述变化可能涉及炎症和内质网应激介导的细胞凋亡和坏死性凋亡。此外,我们在该小鼠模型中评估了临床前药物的功效和 ZIKV 候选疫苗的安全性。我们发现 ZIKV 诱导的视网膜异常可以被选择性黄病毒抑制剂 NITD008 阻断,而活的 ZIKV 减毒候选疫苗可能会诱导视网膜异常。总体而言,我们建立了一种新型小鼠模型,并提供了 ZIKV 与体内视网膜病变之间的直接因果关系,
更新日期:2021-05-25
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