In vivo imaging of Zika virus reveals dynamics of viral invasion in immune-sheltered tissues and vertical propagation during pregnancy
In vivo imaging of Zika virus reveals dynamics of viral invasion in immune-sheltered tissues and vertical propagation during pregnancy
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寨卡病毒的体内成像揭示了病毒侵入免疫保护组织和怀孕期间垂直传播的动态
DOI：
10.7150/thno.43177
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Zheng, Zhenhua
中科院分区：
文献类型：
--
作者：
Wang, Ting;Li, Penghui;Zheng, Zhenhua
基本原理：寨卡病毒（ZIKV）是一种致病性病毒，已知可引起人类广泛的先天性异常，包括小头畸形、格林-巴利综合征、脑膜脑炎和其他神经系统并发症。本研究探讨了ZIKV感染的体内非侵入性检测，这是必要的，以阐明病毒的病毒复制和发病机制，以及加速抗ZIKV.Methods的治疗策略的发展：在这项研究中，重组ZIKV harboring Nluc基因（ZIKV-Nluc）的设计，回收和纯化。在体外和体内，生物发光的水平与病毒载量直接相关。表征了A129（干扰素（IFN）-α/β受体缺陷型）、AG 6（IFN）-α/β和IFN-γ受体缺陷型）和C57 BL/6小鼠中ZIKV感染的动力学。妊娠母鼠在E10时通过足垫内注射感染ZIKV-Nluc。然后，在ZIKV-Nluc病毒感染的小鼠中观察合并的免疫血清（抗ZIKV中和抗体）#22-1。结果：ZIKV-Nluc显示出高遗传稳定性，并且在具有与野生型ZIKV（ZIKVwt）相似性质的细胞中复制良好。在动物器官（包括脾脏、肠、睾丸、子宫/卵巢和肾脏）中始终观察到显著的生物发光信号。发现回盲部是关键的内脏靶点。用ZIKV-Nluc感染妊娠母鼠表明ZIKV能够穿过母胎屏障以通过垂直传播感染胎儿。此外，它是可视化的，与汇集的免疫血清的治疗被发现大大限制了ZIKV-Nluc病毒在mice.Conclusions的传播：这项研究是第一次报告的实时非侵入性跟踪的进展ZIKV入侵免疫庇护组织和垂直传播在怀孕期间。结果表明，ZIKV-Nluc代表了用于研究ZIKV在体外和体内的复制、传播、发病机制和治疗的有力工具。
Rationale: Zika virus (ZIKV) is a pathogenic virus known to cause a wide range of congenital abnormalities, including microcephaly, Guillain-Barre syndrome, meningoencephalitis, and other neurological complications, in humans. This study investigated the noninvasive detection of ZIKV infection in vivo, which is necessary for elucidating the virus's mechanisms of viral replication and pathogenesis, as well as to accelerate the development of anti-ZIKV therapeutic strategies.Methods: In this study, a recombinant ZIKV harbouring Nluc gene (ZIKV-Nluc) was designed, recovered, and purified. The levels of bioluminescence were directly correlated with viral loads in vitro and in vivo. The dynamics of ZIKV infection in A129 (interferon (IFN)-alpha/beta receptor deficient), AG6 (IFN)-alpha/beta and IFN-gamma receptor deficient), and C57BL/6 mice were characterized. Pregnant dams were infected with ZIKV-Nluc at E10 via intra footpad injection. Then, the pooled immune sera (anti-ZIKV neutralizing antibodies) #22-1 in ZIKV-Nluc virus-infected mice were visualized.Results: ZIKV-Nluc showed a high genetic stability and replicated well in cells with similar properties to the wild-type ZIKV (ZIKVwt). Striking bioluminescence signals were consistently observed in animal organs, including spleen, intestine, testis, uterus/ovary, and kidney. The ileocecal junction was found to be the crucial visceral target. Infection of pregnant dams with ZIKV-Nluc showed that ZIKV was capable of crossing the maternal-fetal barrier to infect the fetuses via vertical transmission. Furthermore, it was visualized that treatment with the pooled immune sera was found to greatly restrict the spread of the ZIKV-Nluc virus in mice.Conclusions: This study is the first to report the real-time noninvasive tracking of the progression of ZIKV invading immune-sheltered tissues and propagating vertically during pregnancy. The results demonstrate that ZIKV-Nluc represents a powerful tool for the study of the replication, dissemination, pathogenesis, and treatment of ZIKV in vitro and in vivo.