Characterization of Lethal Zika Virus Infection in AG129 Mice.
Characterization of Lethal Zika Virus Infection in AG129 Mice.
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DOI：
10.1371/journal.pntd.0004682
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发表时间：
2016-04
影响因子：
3.8
通讯作者：
Osorio JE
中科院分区：
文献类型：
--
作者：
Aliota MT;Caine EA;Walker EC;Larkin KE;Camacho E;Osorio JE
蚊媒寨卡病毒（ZIKV）通常会引起一种称为寨卡热的轻度自限性疾病，通常伴有斑丘疹、头痛和肌痛。在南美洲目前的疫情期间，妊娠期间的ZIKV感染被假设为导致小头畸形和其他疾病。胎儿脑组织中ZIKV的检测支持了这一假设。由于人类感染ZIKV在历史上一直是散发性的，并且直到最近才限于小规模流行，因此由ZIKV引起的疾病和毒力和/或致病性的分子决定因素都没有得到很好的表征。在这里，我们描述了亚洲谱系野生型ZIKV的小动物模型。使用干扰素α/β和β受体缺陷的小鼠（AG 129小鼠），我们报告说这些动物对ZIKV感染和疾病高度易感，在七到八天内死亡。在内脏器官和大脑中观察到快速病毒血症传播;但仅与大脑和肌肉中的重度病理相关。最后，这些结果在激发途径、小鼠年龄和接种物剂量之间一致。这些数据代表ZIKV的小鼠模型，其不依赖于使ZIKV适应小鼠脑内传代。用ZIKV对AG 129小鼠进行足垫注射代表了用于研究野生型病毒接种后ZIKV感染和疾病发展的生物学相关模型，而不需要病毒的适应或病毒的脑内递送。这种新开发的寨卡病模型可用于鉴定ZIKV毒力的决定因素，并揭示控制病毒与宿主相互作用的分子机制，为合理设计急性期治疗方法和疫苗功效测试提供框架。寨卡病毒（ZIKV）是一种属于黄病毒科的虫媒病毒。它目前正在美洲引起发热性疾病的爆发。在人类中，ZIKV感染通常会引起一种称为寨卡热的轻度自限性疾病，通常伴有斑丘疹，头痛和肌痛。在目前的疫情中，怀孕期间的ZIKV感染被假设会导致小头畸形和其他疾病。胎儿脑组织中ZIKV的检测支持这一假设。我们对控制ZIKV毒力和发病机制的分子机制的理解是有限的，由于缺乏不依赖于脑内接种病毒的小动物模型，进展受到极大阻碍。在这里，我们证明了野生型ZIKV，这是目前在南美洲流行的亚洲谱系的代表，在干扰素α/β和β受体缺陷的小鼠中引起致命疾病。在这些动物中，ZIKV引起严重的脑病理学，潜在地模仿人胎儿ZIKV感染的标志性特征。这种新开发的寨卡病模型可用于鉴定ZIKV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，为合理设计急性期治疗和疫苗有效性测试提供框架。
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. 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. 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. Zika virus (ZIKV) is an arbovirus that belongs to the family Flaviridae. It currently is causing an explosive outbreak of febrile disease in the Americas. In humans, ZIKV infection 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, ZIKV infection during pregnancy has been hypothesized to cause microcephaly and other diseases. The detection of ZIKV in fetal brain tissue supports this hypothesis. Our understanding of the molecular mechanisms controlling ZIKV virulence and pathogenesis is limited, with progress greatly impeded by the lack of a small animal model that does not rely on intracerebral inoculation of the virus. Here, we demonstrate that wild-type ZIKV, that is representative of the Asian lineage currently circulating in South America, causes lethal disease in mice deficient in interferon α/β and Ɣ receptors. In these animals, ZIKV causes severe brain pathology, potentially emulating hallmark features of human fetal ZIKV infection. 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.