Flaviviruses such as Zika virus and West Nile virus have the potential to cause severe neuropathology if they invade the central nervous system. The type I interferon response is well characterized as contributing to control of flavivirus-induced neuropathogenesis. However, the interferon-stimulated gene (ISG) effectors that confer these neuroprotective effects are less well studied. Here, we used an ISG expression screen to identify Shiftless (SHFL, C19orf66) as a potent inhibitor of diverse positive-stranded RNA viruses, including multiple members of the Flaviviridae (Zika, West Nile, dengue, yellow fever, and hepatitis C viruses). In cultured cells, SHFL functions as a viral RNA-binding protein that inhibits viral replication at a step after primary translation of the incoming genome. The murine ortholog, Shfl, is expressed constitutively in multiple tissues, including the central nervous system. In a mouse model of Zika virus infection, Shfl^−/− knockout mice exhibit reduced survival, exacerbated neuropathological outcomes, and increased viral replication in the brain and spinal cord. These studies demonstrate that Shfl is an important antiviral effector that contributes to host protection from Zika virus infection and virus-induced neuropathological disease.

寨卡病毒和西尼罗河病毒等黄病毒如果侵入中枢神经系统，就有可能导致严重的神经病理学。I 型干扰素反应被很好地表征为有助于控制黄病毒诱导的神经发病机制。然而，赋予这些神经保护作用的干扰素刺激基因 (ISG) 效应器的研究较少。在这里，我们使用 ISG 表达筛选来鉴定 Shiftless（SHFL，C19orf66）作为多种正链 RNA 病毒（包括黄病毒科的多个成员）的有效抑制剂（寨卡病毒、西尼罗河病毒、登革热病毒、黄热病病毒和丙型肝炎病毒）。在培养的细胞中，SHFL 作为病毒 RNA 结合蛋白发挥作用，在传入基因组的初级翻译后的一个步骤中抑制病毒复制。鼠直系同源物 Shfl 在包括中枢神经系统在内的多种组织中组成型表达。在寨卡病毒感染的小鼠模型中，Shfl ^-/-基因敲除小鼠的存活率降低，神经病理学结果恶化，大脑和脊髓中的病毒复制增加。这些研究表明，Shfl 是一种重要的抗病毒效应物，有助于宿主保护免受寨卡病毒感染和病毒诱导的神经病理学疾病。