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

寨卡病毒(Zika Virus，ZIKV)属于黄病毒科黄病毒属，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。虽然大多数寨卡病毒感染都是无症状的，但由于最近的大流行蔓延以及它被认为是导致严重神经系统并发症的重要人类病原体，最明显的是小头畸形症，ZIKV已经得到了越来越多的公众认识。虽然ZIKV的神经亲和性越来越明显，但其发病的分子机制在很大程度上还不清楚。我们最近发现，ZIKV感染人神经前体细胞会引发深刻的细胞骨架重排。此外，我们和其他人发现，致病的ZIKV毒株似乎获得了独特的突变，这可能有助于病理。基于这些发现，我们将研究ZIKV感染诱导细胞损伤的机制，以及ZIKV进化在这一过程中所起的作用。在海德堡的Bartenschlager实验室和上海的Long实验室的密切合作下，我们将使用体外和体内模型来研究两种互补和相互关联的方法。第一部分阐述了ZIKV诱导的细胞骨架改变的机制以及对神经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适合性和神经发病机制中发挥作用，以及这些突变可能如何影响神经细胞的细胞骨架变化。通过这种方式，我们的目标是定位和表征负责细胞骨架依赖和非独立神经发病的病毒决定因素。

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.