Yerkes National Primate Research Center Role of type-I IFN in regulating COVID-19 induced inflammation and pathogenesis

修订后的标题： 耶尔克斯国家灵长类动物研究中心I型干扰素在新冠肺炎诱导的炎症和发病机制中的调节作用 修订摘要： 这是耶克斯国家灵长类动物研究中心(YNPRC)的行政补充。该补充剂的目标是对总共30只恒河猴进行研究，其中15只冠状病毒感染的“对照”动物与15只接受I型干扰素拮抗剂治疗的冠状病毒感染的猕猴进行比较，以增加疾病的严重性。最近的研究表明，由于病毒传播失控和过度炎症，I型干扰素反应缺陷可能会导致严重的、危及生命的新冠肺炎结局。感染SARS-CoV-2的恒河猴出现轻到中度的COVID，实验治疗的目的是在这个NHP模型中诱导更严重的疾病，以测试潜在的治疗方法。提出了一种适应性试验设计，以使用最少的动物数量来提供统计功率意愿。将在连续时间点从动物身上收集广泛的病毒、分子、细胞、免疫学和临床终点，还将在动物亚群的连续尸检中采集几个组织/器官(所有剩余动物的末期尸检)。这些样本中的许多将由两个不同的实验室进行组织学和/或通过分子和其他方法进行研究，以测试和开发NPRC新冠肺炎标准操作规程并评估重复性。样本还将作为资源被生物储存起来，供其他研究人员未来使用。调查团队和环境被认为是一流的。该项目被认为是高度优先的，因为它对于了解COVID的炎性后遗症，开发严重疾病的恒河猴模型，以及跨NPR开展工作并获得相关专业知识以推进标准化的SOP具有重要意义。这项工作应该提供对发病机制和炎症途径的深入了解，这将是测试候选疗法和第二代/第三代疫苗的关键。

Revised Title: Yerkes National Primate Research Center Role of type-I IFN in regulating COVID-19 induced inflammation and pathogenesis Revised Abstract: This is an administrative supplement from the Yerkes National Primate Research Center (YNPRC). The goal of the supplement is to conduct a study with a total of 30 rhesus macaques in which 15 CoV-infected “control” animals are compared to 15 CoV-infected macaques treated with type I IFN antagonist to increase disease severity. Recent studies suggest that a defective type-I IFN response may cause severe and life-threatening COVID-19 outcomes due to uncontrolled viral spread and excessive inflammation. SARS-CoV-2-infected rhesus macaques develop mild to moderate COVID, and the aim of the experimental treatment is to induce more severe disease in this NHP model to test potential therapeutics. An adaptive trial design is proposed to provide statistical power will using the fewest number of animals. A wide range of viral, molecular, cellular, immunological, and clinical endpoints will be collected from the animals at serial timepoints and several tissues/organs will also be sampled in serial necropsies in subsets of animals (terminal necropsies in all remaining animals). Many of these samples will be investigated histologically and/or via molecular and other approaches by two different labs to test and develop NPRC COVID-19 SOPs and assess reproducibility. Samples will also be bio-banked as resources for future use by other researchers. The investigative team and environment are considered excellent. The project is considered high priority due to its importance for understanding the inflammatory sequalae of COVID, developing a rhesus model of severe disease, and working across NPRCs and accessing relevant expertise to advance standardized SOPs. This work should provide an in depth understanding of pathogenesis and inflammatory pathways, which will be critical to testing candidate therapeutics and second/third generation vaccines.