Aliota Matthew T, Caine Elizabeth A, Walker Emma C, Larkin Katrina E, Camacho Erwin, Osorio Jorge E
Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
PLoS Negl Trop Dis. 2016 Apr 19;10(4):e0004682. doi: 10.1371/journal.pntd.0004682. eCollection 2016 Apr.
Mosquito-borne Zika virus (ZIKV) typically causes a mild and self-limiting illness known as Zika fever, which often is accompanied by maculopapular rash, headache, and myalgia. During the current outbreak in South America, ZIKV infection during pregnancy has been hypothesized to cause microcephaly and other diseases. The detection of ZIKV in fetal brain tissue supports this hypothesis. Because human infections with ZIKV historically have remained sporadic and, until recently, have been limited to small-scale epidemics, neither the disease caused by ZIKV nor the molecular determinants of virulence and/or pathogenicity have been well characterized. Here, we describe a small animal model for wild-type ZIKV of the Asian lineage.
METHODOLOGY/PRINCIPAL FINDINGS: Using mice deficient in interferon α/β and Ɣ receptors (AG129 mice), we report that these animals were highly susceptible to ZIKV infection and disease, succumbing within seven to eight days. Rapid viremic dissemination was observed in visceral organs and brain; but only was associated with severe pathologies in the brain and muscle. Finally, these results were consistent across challenge routes, age of mice, and inoculum doses. These data represent a mouse model for ZIKV that is not dependent on adapting ZIKV to intracerebral passage in mice.
CONCLUSIONS/SIGNIFICANCE: Foot pad injection of AG129 mice with ZIKV represents a biologically relevant model for studying ZIKV infection and disease development following wild-type virus inoculation without the requirement for adaptation of the virus or intracerebral delivery of the virus. This newly developed Zika disease model can be exploited to identify determinants of ZIKV virulence and reveal molecular mechanisms that control the virus-host interaction, providing a framework for rational design of acute phase therapeutics and for vaccine efficacy testing.
蚊媒传播的寨卡病毒（ZIKV）通常引起一种称为寨卡热的轻度自限性疾病，常伴有斑丘疹、头痛和肌痛。在当前南美洲的疫情中，有人推测孕期感染寨卡病毒会导致小头畸形和其他疾病。在胎儿脑组织中检测到寨卡病毒支持了这一推测。由于人类感染寨卡病毒在历史上一直呈散发性，直到最近也仅限于小规模流行，因此寨卡病毒所致疾病以及毒力和/或致病性的分子决定因素均未得到充分表征。在此，我们描述了一种针对亚洲谱系野生型寨卡病毒的小动物模型。
方法/主要发现：利用缺乏干扰素α/β和γ受体的小鼠（AG129小鼠），我们发现这些动物对寨卡病毒感染和疾病高度易感，在7至8天内死亡。在内脏器官和脑中观察到病毒血症迅速扩散；但仅与脑和肌肉中的严重病变相关。最后，这些结果在不同的感染途径、小鼠年龄和接种剂量下均一致相同。这些数据代表了一种不依赖于将寨卡病毒适应小鼠脑内传代的寨卡病毒小鼠模型。
结论/意义：通过足垫注射将寨卡病毒接种到AG129小鼠体内，代表了一种生物学上相关的模型，用于研究野生型病毒接种后寨卡病毒感染和疾病发展，而无需对病毒进行适应或通过脑内递送病毒。这种新开发的寨卡疾病模型可用于确定寨卡病毒毒力的决定因素，并揭示控制病毒-宿主相互作用的分子机制，为急性期治疗药物的合理设计和疫苗疗效测试提供框架。
