ZIKA VIRUS RESISTANCE; HOST DETERMINANTS

项目摘要 寨卡病毒（ZIKV）是一种主要通过蚊子传播给人类宿主的黄病毒。大多数个体 ZIKV感染者仍无症状。在极少数情况下，ZIKV感染可能与格林-巴利综合征有关。 综合症，甚至在更罕见的情况下，死亡。然而，孕妇感染可导致 ZIKV经胎盘传播给胎儿，导致小头畸形，如在最近的爆发中观察到的 在南美洲和中美洲。目前还没有针对ZIKV的抗病毒治疗或疫苗，开发一种 因此，理解ZIKV感染的发病机理具有极高的优先级。我们最近 鉴定出缺乏ISG 15或USP 18的人，ISG 15或USP 18是I型IFN的两种重要下调因子 信号通路我们的初步数据显示，ISG 15和USP 18缺陷细胞系比正常细胞系更容易发生凋亡。 与野生型（WT）细胞系相比，具有ZIKV抗性的细胞系。我们的初步数据来自ISG 15缺陷的细胞 个体已经表明，只有少数干扰素刺激的基因（ISG）参与控制 ZIKV感染。在本建议书所述的工作中，我们会修订参与管制 通过比较ISG 15-和USP 18-缺陷细胞与WT细胞，观察ZIKV感染。这将使我们有可能 进一步缩小可能参与抗ZIKV应答的ISG数量，从400多个减少到 <20.我们将鉴定和表征限制ZIKV感染的主要因素，在RNA（目的1）和 蛋白质（Aim 2）水平。然后，我们将评估七种ZIKV毒株在小鼠中诱导I型IFN产生的能力。 不同的细胞类型，以及它们对I型IFN治疗的敏感性。通过提高我们对 ZIKV耐药性的人类决定因素，我们应该能够开发关于两者的新假设 人体体内易感性和药物开发。

PROJECT SUMMARY Zika virus (ZIKV) is a flavivirus that is transmitted to its human host principally by mosquitos. Most individuals infected with ZIKV remain asymptomatic. In rare cases, ZIKV infection may be associated with Guillain-Barre syndrome and, in even rarer cases, death. However, infections in pregnant women can result in the transplacental transmission of ZIKV to the fetus, leading to microcephaly, as observed in the recent outbreaks in South and Central America. There is currently no antiviral treatment or vaccine for ZIKV, and developing an understanding of the pathogenesis of ZIKV infections is, thus, of extremely high priority. We have recently identified humans with deficiencies of either ISG15 or USP18, two important downregulators of the type I IFN signaling pathway. Our preliminary data have revealed that ISG15- and USP18-deficient cell lines are more resistant to ZIKV than wild-type (WT) cell lines. Our preliminary data for cells derived from ISG15-deficient individuals have shown that only a handful of interferon-stimulated genes (ISGs) are involved in controlling ZIKV infection. In the work described in this proposal, we will refine the list of ISGs involved in the control of ZIKV infection, by comparing ISG15- and USP18-deficient cells with WT cells. This should make it possible to further narrow down the number of ISGs potentially involved in the anti-ZIKV response from more than 400 to <20. We will identify and characterize the principal factors restricting ZIKV infection, at the RNA (Aim 1) and protein (Aim 2) levels. We will then assess the ability of seven ZIKV strains to induce type I IFN production in different cell types, and their sensitivity to treatment with type I IFN. By improving our understanding of the human determinants of ZIKV resistance, we should be able to develop new hypotheses concerning both human susceptibility in vivo and drug development.