Discovery of antiviral mechanisms in bats

描述（由申请方提供）：抗病毒干扰素提供了抵抗病毒感染的关键宿主防御机制。在没有IFN信号传导的情况下，宿主可能易受致死性病毒感染。IFN通过转录诱导保护宿主细胞免受病毒性疾病的侵害 数百个干扰素刺激的基因，其编码多种直接的抗病毒效应物和宿主防御信号通路的调节剂。我们最近的筛选工作旨在鉴定新型人类抗病毒ISG，表征其作用机制，并确定其在广泛的高度多样化病毒中的特异性。感兴趣的病毒包括正在出现或重新出现的传染病威胁的几种病原体。这些病毒中有许多是从天然动物宿主传播给人类的。在众多的水库主机，蝙蝠是特别独特的能力，窝藏高致病性病毒，几乎没有明显的疾病。蝙蝠抵抗病毒性疾病的机制基础目前尚不清楚，但有几条证据指向一个潜在的独特的先天免疫系统。该项目的目标是建立一个蝙蝠ISG发现管道，重点是识别和表征新的抗病毒机制。在实验上，我们将使用现有的蝙蝠基因组数据合成靶向蝙蝠ISG文库。同时，我们将建立从IFN处理的蝙蝠细胞中富集抗病毒ISG的方法。我们之前的基于细胞的流式细胞术筛选平台将被小型化，用于快速测试蝙蝠ISG对各种蝙蝠和人类细胞系中的多种病毒的抵抗。后续机制研究包括使用分子病毒学工具来确定ISG在病毒生命周期中的作用模式，以及生物化学、遗传学和细胞生物学方法来揭示基于宿主的抗病毒作用机制。

DESCRIPTION (provided by applicant): Antiviral interferons provide critical host defense mechanisms against viral infection. In the absence of IFN signaling, the host may be susceptible to lethal viral infection. IFNs protect host cells from viral disease by transcriptionally inducing hundreds of interferon-stimulated genes, which encode a variety of direct antiviral effectors and modulators of host defense signaling pathways. Our recent screening efforts have sought to identify novel human antiviral ISGs, characterize their mechanisms of action, and determine their specificity across a broad range of highly diverse viruses. The viruses of interest include several pathogens that are emerging or re-emerging infectious disease threats. Many of these viruses are transmitted to humans from natural animal reservoirs. Among the numerous reservoir hosts, bats are particularly unique in their ability to harbor highly pathogenic viruses with little to no overt disease. The mechanistic basis for the resistance of bats to viral disease s currently unknown, but several lines of evidence point to a potentially unique innate immune system. The goals of this project are to institute a bat ISG discovery pipeline, with an emphasis on the identification and characterization of novel antiviral mechanisms. Experimentally, we will synthesize a targeted bat ISG library using available bat genomic data. In parallel, we will establish methods for antiviral ISG enrichment from IFN-treated bat cells. Our previous cell-based flow cytometry screening platform will be miniaturized for rapid testing of bat ISGs against numerous viruses in a variety of bat and human cell lines. Follow-up mechanistic studies include the use of molecular virological tools to determine ISG modes of action in the viral life cycle, in addition to biochemical, genetic, and cell biological approaches to uncover th host-based mechanisms of antiviral action.