Nebraska Center for Virology, University of Nebraska, Lincoln, Nebraska, USA.
Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, Nebraska, USA.
J Biol Chem. 2020 Dec 11;295(50):17114-17127. doi: 10.1074/jbc.RA120.015165. Epub 2020 Oct 7.
Zika virus (ZIKV) is a neurotropic flavivirus that causes several diseases including birth defects such as microcephaly. Intrinsic immunity is known to be a frontline defense against viruses through host anti-viral restriction factors. Limited knowledge is available on intrinsic immunity against ZIKV in brains. Amyloid precursor protein (APP) is predominantly expressed in brains and implicated in the pathogenesis of Alzheimer's diseases. We have found that ZIKV interacts with APP, and viral infection increases APP expression via enhancing protein stability. Moreover, we identified the viral peptide, HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL, which is capable of en-hancing APP expression. We observed that aging brain tissues with APP had protective effects on ZIKV infection by reducing the availability of the viruses. Also, knockdown of APP expression or blocking ZIKV-APP interactions enhanced ZIKV replication in human neural progenitor/stem cells. Finally, intracranial infection of ZIKV in APP-null neonatal mice resulted in higher mortality and viral yields. Taken together, these findings suggest that APP is a restriction factor that protects against ZIKV by serving as a decoy receptor, and plays a protective role in ZIKV-mediated brain injuries.
寨卡病毒（ZIKV）是一种神经嗜性黄病毒，可引起多种疾病，包括小头畸形等出生缺陷。固有免疫被认为是通过宿主抗病毒限制因子对病毒的第一道防线。目前对大脑中针对 ZIKV 的固有免疫知之甚少。淀粉样前体蛋白（APP）主要在大脑中表达，并与阿尔茨海默病的发病机制有关。我们发现 ZIKV 与 APP 相互作用，病毒感染通过增强蛋白质稳定性增加 APP 表达。此外，我们鉴定了能够增强 APP 表达的病毒肽 HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL。我们观察到具有 APP 的衰老脑组织通过减少病毒的可用性对 ZIKV 感染具有保护作用。此外，敲低 APP 表达或阻断 ZIKV-APP 相互作用可增强人神经祖细胞/干细胞中的 ZIKV 复制。最后，在 APP 缺失的新生小鼠中颅内感染 ZIKV 导致更高的死亡率和病毒产量。总之，这些发现表明 APP 是一种限制因子，通过充当诱饵受体来保护免受 ZIKV 感染，并在 ZIKV 介导的脑损伤中发挥保护作用。
