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

I 型干扰素在调节 COVID-19 诱导的炎症和发病机制中的作用

基本信息

批准号：
10321484
负责人：
JONATHAN S LEWIN
金额：
$ 78.45万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-23 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321484
关键词：
2019-nCoV Achievement Acute Address Animal Model Animals Antiviral Agents Antiviral Response Ants Autopsy Biological Models Blood Brain COVID-19 COVID-19 morbidity COVID-19 mortality COVID-19 screening COVID-19 treatment Cardiomyopathies Caring Cells Cessation of life Chronic Clinic Clinical Controlled Study Coronavirus Coughing Data Development Disease Progression Disease model Exhibits Fever Genes Genomics Goals Heart Hereditary Disease Hospitals Human Image Immune Immune response Immunoglobulin G Immunologics Immunology Immunomodulators Individual Infection Inflammasome Inflammation Inflammatory Inflammatory Response Interferon Type I Interferons Intervention Lead Leadership Life Link Lower respiratory tract structure Lung Lung Inflammation Macaca mulatta Middle East Respiratory Syndrome Modeling Molecular Mucous Membrane Multiple Organ Failure Outcome Pathogenesis Pathology Pathway interactions Patients Phase Pneumonia Preclinical Testing Reproducibility Respiratory Failure Respiratory Tract Infections Roentgen Rays Role SARS-CoV-2 infection SARS-CoV-2 pathogenesis SARS-CoV-2 transmission Sampling Series Serum Severe Acute Respiratory Syndrome Severity of illness Signal Transduction Specimen Standardization Swab Symptoms Testing Therapeutic Tissues Translating Tumor-infiltrating immune cells Universities Vaccines Validation Viral Viral Pathogenesis Virus Virus Replication Work biosafety level 3 facility chemokine coronavirus disease cytokine design effective therapy efficacy study immune activation in vivo inflammatory marker insight interdisciplinary approach longitudinal analysis loss of function member nonhuman primate pandemic disease preclinical study prevent response severe COVID-19 systemic inflammatory response therapeutic candidate therapeutic evaluation vaccine evaluation virology virtual

项目摘要

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.

抽象的随着患者数量的增加，SARS-CoV-2 继续以指数速度在全球传播在医院里。由于传播迅速，关于病毒发病机制和宿主仍有许多待了解对感染的免疫反应。 COVID-19 进展的免疫学特征包括强大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) 信号传导缺陷与危及生命的 COVID-19 结局相关以前健康的人。建立严重 SARS-CoV-2 感染的非人类灵长类动物模型可能对于了解 SARS-CoV-2 发病机制以及候选抗病毒药物和免疫的临床前测试调节剂能够减少病毒复制的程度和过度炎症。在此，我们是提议对感染 SARS-CoV-2 的恒河猴进行广泛且最先进的免疫学分析（RM）来识别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，我们将在体内特异性地直接阻断，类型- 通过施用 I 型 IFN 拮抗剂（IFN-I）对 SARS-CoV-2 感染的 RM 产生 I IFN 反应（目标 #2）蚂蚁）。该干预措施将阐明 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 蚂蚁治疗是否可以建立严重且可重复的 NHP COVID-19 模型。此外，纵向和尸检时收集的标本将被冷冻保存在 COVTEN 联盟之间共享和使用，用于验证已建立的 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，包括非常感染后早期，跨多个组织，包括肺、心脏和大脑，将使我们能够解决我们的问题具有深度和严格性的关键问题实际上是人类不可能实现的。这些成就将为 SARS-CoV-2 发病机制提供重要见解，并将提供强有力的研究 NHP 模型用于优先考虑并加速最有前途候选药物的开发疗法。这项研究将交叉验证 COVTEN SOP 并建立一个强大的模型供 ACTIV 联盟。