Visualization of a neurotropic flavivirus infection in mouse reveals unique viscerotropism controlled by host type I interferon signaling.
Visualization of a neurotropic flavivirus infection in mouse reveals unique viscerotropism controlled by host type I interferon signaling.
复制标题
小鼠嗜神经黄病毒感染的可视化揭示了由宿主 I 型干扰素信号控制的独特的趋内脏性
作者：
Li XF;Li XD;Deng CL;Dong HL;Zhang QY;Ye Q;Ye HQ;Huang XY;Deng YQ;Zhang B;Qin CF
黄病毒包括一大组具有医学重要性的人类病原体。特别是，能够侵入中枢和外周神经系统的嗜神经性黄病毒，例如日本脑炎病毒（JEV）和寨卡病毒（ZIKV），对人类具有高致病性，并构成主要的全球健康问题。然而，嗜神经黄病毒感染的动态传播和发病机制在很大程度上仍然未知。在这里，使用JEV作为模型，我们合理地设计并构建了稳定表达海肾荧光素酶（Rluc）的重组报告病毒。所得到的JEV报告病毒（命名为Rluc-JEV）和亲本JEV表现出相似的复制和感染特征，并且Rluc活性的大小与体内和体外的子代病毒产生良好相关。利用体内生物发光成像技术，研究了不同接种途径下JEV在小鼠体内的复制和传播动态。有趣的是，除了在小鼠脑中复制外，Rluc-JEV主要侵袭具有典型向内脏性的小鼠的腹部器官。在缺乏I型干扰素（IFN）受体的小鼠中进行的进一步测试表明，在肠、脾、肝、肾和其他腹部器官中病毒复制稳健且延长。结合组织病理学和免疫组化结果，证明宿主I型IFN信号是这种嗜神经黄病毒嗜内脏性和致病性的主要障碍。此外，Rluc-JEV平台易于适用于已知抗病毒化合物和活JE疫苗的功效测定。总的来说，我们的研究揭示了腹部器官作为JEV感染小鼠的重要靶点，并描述了由宿主I型IFN信号转导控制的独特向内脏性特征。本文描述的这种体内可视化技术为测试黄病毒感染的抗病毒剂和候选疫苗提供了有力的工具。
Flavivirus includes a large group of human pathogens with medical importance. Especially, neurotropic flaviviruses capable of invading central and peripheral nervous system, e.g. Japanese encephalitis virus (JEV) and Zika virus (ZIKV), are highly pathogenic to human and constitute major global health problems. However, the dynamic dissemination and pathogenesis of neurotropic flavivirus infections remain largely unknown. Here, using JEV as a model, we rationally designed and constructed a recombinant reporter virus that stably expressed Renilla luciferase (Rluc). The resulting JEV reporter virus (named Rluc-JEV) and parental JEV exhibited similar replication and infection characteristics, and the magnitude of Rluc activity correlated well with progeny viral production in vitro and in vivo. By using in vivo bioluminescence imaging (BLI) technology, we dissected the replication and dissemination dynamics of JEV infection in mice upon different inoculation routes. Interestingly, besides replicating in mouse brain, Rluc-JEV predominantly invaded the abdominal organs in mice with typical viscerotropism. Further tests in mice deficient in type I interferon (IFN) receptors demonstrated robust and prolonged viral replication in the intestine, spleen, liver, kidney and other abdominal organs. Combined with histopathological and immunohistochemical results, the host type I IFN signaling was evidenced as the major barrier to the viscerotropism and pathogenicity of this neurotropic flavivirus. Additionally, the Rluc-JEV platform was readily adapted for efficacy assay of known antiviral compounds and a live JE vaccine. Collectively, our study revealed abdominal organs as important targets of JEV infection in mice and profiled the unique viscerotropism trait controlled by the host type I IFN signaling. This in vivo visualization technology described here provides a powerful tool for testing antiviral agents and vaccine candidates for flaviviral infection.