Molecular mechanisms of Zika virus-associated neuropathogenesis and possible link to virus evolution

寨卡病毒相关神经发病机制的分子机制及其与病毒进化的可能联系

• 批准号: 391587080
• 负责人: Professor Dr. Ralf Friedrich Wilhelm Bartenschlager
• 金额: --
• 依托单位: National Natural Science Foundation of China
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/391587080?language=en
• 关键词: Molecular; mechanisms; Zika; virus; associated

Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family, which includes other globally relevant arthropod-transmitted human pathogens such as dengue virus and yellow fever virus. Although the majority of ZIKV infections are asymptomatic, ZIKV has received increasing public awareness because of its recent pandemic spread and its recognition as an important human pathogen causing severe neurological complications, most notably microcephaly. While the neurotropism of ZIKV is becoming increasingly clear, the molecular mechanisms underlying this pathogenesis are largely unknown. We have recently found that infection of human neural progenitor cells with ZIKV triggers profound cytoskeletal rearrangements. Moreover, we and others found that pathogenic ZIKV strains appear to have acquired distinct mutations that might contribute to pathologies. Based on these findings in this proposal we will examine the mechanisms underlying ZIKV infection-induced cell damage as well as the role of ZIKV evolution for this process. In close collaboration between the Bartenschlager laboratory in Heidelberg and the Long laboratory in Shanghai we will employ in vitro and in vivo models to study two complementary and inter-related approaches. The first one addresses the mechanism of ZIKV-induced alterations of the cytoskeleton and the consequences for neuronal cells and their development. The second approach takes advantage of a newly developed ZIKV infectious clone and aims to determine whether ZIKV mutations identified in patients with severe infections play a role in ZIKV fitness and neuro-pathogenesis and how these mutations might impact on cytoskeleton alterations of neuronal cells. In this way we aim to map and characterize the viral determinants responsible for cytoskeleton-dependent and -independent neuropathogenesis.

寨卡病毒（ZIKV）属于黄病毒科的黄病毒属，包括其他全球相关的节肢动物传播的人类病原体，如登革热病毒和黄热病病毒。尽管大多数ZIKV感染是无症状的，但由于其最近的大流行传播及其被认为是引起严重神经系统并发症（最显著的是小头畸形）的重要人类病原体，ZIKV已获得越来越多的公众意识。虽然ZIKV的嗜神经性变得越来越清楚，但这种发病机制的分子机制在很大程度上是未知的。我们最近发现，ZIKV感染人神经祖细胞引发了深刻的细胞骨架重排。此外，我们和其他人发现，致病性ZIKV毒株似乎已经获得了可能导致病理的不同突变。基于本提案中的这些发现，我们将研究ZIKV感染诱导的细胞损伤的潜在机制以及ZIKV进化在该过程中的作用。在海德堡Bartenschlager实验室和上海Long实验室的密切合作下，我们将采用体外和体内模型来研究两种互补和相互关联的方法。第一个解决了ZIKV诱导的细胞骨架改变的机制以及对神经元细胞及其发育的影响。第二种方法利用新开发的ZIKV感染性克隆，旨在确定在严重感染患者中发现的ZIKV突变是否在ZIKV适应性和神经发病机制中发挥作用，以及这些突变如何影响神经元细胞的细胞骨架改变。通过这种方式，我们的目标是映射和表征负责细胞因子依赖性和非依赖性神经发病的病毒决定因素。