Role of type-I IFN in regulating COVID-19 induced inflammation and pathogenesis

摘要 SARS-CoV-2继续以指数速度在地球仪传播，患者人数不断增加 在医院由于传播迅速，关于病毒的发病机制和宿主仍有许多问题有待了解 对感染的免疫反应。COVID-19进展的免疫学特征包括一种强有力的亲- 由先天性和适应性免疫细胞驱动的炎症反应。重要的是，最近的研究表明， I型干扰素（IFN）信号传导的缺陷与危及生命的COVID-19结果相关， 以前健康的人。 建立严重SARS-CoV-2感染的非人灵长类动物模型可能被证明是必要的， 了解SARS-CoV-2的发病机制，并用于候选抗病毒药物和免疫的临床前测试 能够降低病毒复制和过度炎症程度的调节剂。在此，我们是 提出了在SARS-CoV-2感染的恒河猴中进行广泛和最先进的免疫学分析， (RMs)确定炎症和疾病严重程度的标志物，可用于开发标准化和 COVID-19的稳健RM/NHP模型（目标#1）。此外，我们将专门和直接在体内阻断- 通过施用I型IFN拮抗剂（IFN-I）在SARS-CoV-2感染的RM中的I型IFN应答（目的#2） ant）。这种干预将阐明I型IFN在保护宿主免受严重COVID-19感染方面的作用 进展，并研究短期IFN-I抗治疗是否可以建立一个严重的和可重复的NHP COVID-19模型。此外，纵向和尸检时采集的标本将进行冷冻存库， 在COVTEN联合体中共享和使用，以验证既定SOP以及解决 与COVID-19炎症和发病机制相关的其他问题。 纵向追踪发病机制、免疫反应和病毒复制的优势，包括非常重要的 在感染后早期，在多个组织，包括肺，心脏和大脑，将使我们能够解决我们的问题。 这些问题的深度和严谨性在人类身上几乎是不可能实现的。这些成就 将为SARS-CoV-2发病机制提供关键的见解，并将提供一个强大的 NHP模型，用于优先考虑并加速最有前途的候选人的开发 治疗学本研究将交叉验证COVTEN SOP，并建立一个稳健的模型，供 ACTIV财团。

Abstract SARS-CoV-2 continues to spread across the globe at an exponential rate with increasing numbers of patients in the hospital. Due to the rapid spread, much remains to be understood about viral pathogenesis and host immune response to infection. Immunological features of COVID-19 progression include a robust pro- inflammatory response driven by innate and adaptive immune cells. Importantly, very recent studies suggest that deficiency in type-I interferon (IFN) signaling is associated with life-threatening COVID-19 outcomes in previously healthy individuals. Establishment of a non-human primate model of severe SARS-CoV-2 infection could prove essential for understanding SARS-CoV-2 pathogenesis and for preclinical testing of candidate antiviral agents and immune modulators able to reduce the extent of viral replication and the excessive inflammation. Herein, we are proposing extensive and state-of-the-art immunologic analyses in SARS-CoV-2 infected rhesus macaques (RMs) to identify markers of inflammation and disease severity that can be used to develop a standardized and robust RM/NHP model of COVID-19 (Aim #1). Furthermore, we will block, specifically and directly in vivo, type- I IFN responses in SARS-CoV-2-infected RMs (Aim #2) via administration of a type-I IFN antagonist (IFN-I ant). This intervention will elucidate the roles of type-I IFN in protecting the host from severe COVID-19 progression and investigate if a short-term IFN-I ant treatment can establish a severe and reproducible NHP COVID-19 model. Additionally, specimens collected longitudinally and at necropsy will be cryo-banked to be shared and used among the COVTEN consortium for validation of established SOPs as well as for addressing additional questions related to COVID-19 inflammation and pathogenesis. The advantage of tracking pathogenesis, immune responses, and viral replication longitudinally, including very early after infection, and across multiple tissues, including lung, heart, and brain, will allow us to address our critical questions with a depth and rigor that is virtually impossible to achieve in humans. These achievements will provide key insights into the mechanisms of SARS-CoV-2 pathogenesis, and will deliver a robust NHP model for prioritizing and accelerating the development of the most promising candidate therapeutics. This study will cross-validate COVTEN SOPs and establish a robust model to be utilized by the ACTIV consortium.