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

• 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
• 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

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 SARS-COV-2继续以指数率的速度遍及全球，患者人数越来越多 在医院。由于迅速的扩散，关于病毒发病机理和宿主仍有许多待理解 对感染的免疫反应。 COVID-19进展的免疫学特征包括强大的预科 由先天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）信号的缺乏与威胁生命的Covid-19结果有关 以前健康的个体。 建立严重SARS-COV-2感染的非人类灵长类动物模型可能对 了解SARS-COV-2发病机理和用于候选抗病毒药和免疫的临床前测试 能够减少病毒复制程度和过度炎症程度的调节剂。在这里，我们是 在SARS-COV-2感染的恒河猕猴中提出广泛和最先进的免疫学分析 （RMS）确定可用于开发标准化和疾病严重程度的标志物 COVID-19的强大RM/NHP模型（AIM＃1）。此外，我们将在体内进行专门和直接阻止类型 - I IFN感染的RMS中的I IFN响应（AIM＃2）通过施用I型IFN拮抗剂（IFN-I 蚂蚁）。这种干预将阐明I型IFN在保护宿主免受严重covid-19的影响中的作用 进展并研究短期IFN-I ANT治疗是否可以建立严重且可重复的NHP COVID-19模型。此外，纵向收集的标本和在死灵尸体时将被冷冻储备为 在Covten联盟中共享和使用，以验证已建立的SOP以及解决 与COVID-19的炎症和发病机理有关的其他问题。 跟踪发病机理，免疫反应和病毒复制的优势，包括非常 感染后的早期以及包括肺，心脏和大脑在内的多个组织，将使我们能够解决我们的问题 在人类中几乎无法实现的深度和严格问题的关键问题。这些成就 将提供有关SARS-COV-2发病机理机制的关键见解，并将提供强大的 NHP模型，用于优先和加速最有前途的候选人的发展 疗法。这项研究将交叉估算Covten SOP并建立一个可靠的模型 活动联盟。