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.

摘要 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。由于病毒的迅速传播，对病毒的致病机制和宿主仍有许多需要了解的地方。 对感染的免疫反应。新冠肺炎进展的免疫学特征包括强大的PRO-2 先天免疫细胞和获得性免疫细胞驱动的炎症反应。重要的是，最近的研究表明 I型干扰素信号传递的缺陷与危及生命的新冠肺炎预后相关 以前健康的个体。 建立严重SARS-CoV-2感染的非人灵长类动物模型可能对 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 调节剂能够减少病毒复制的程度和过度炎症。在这里，我们是 对感染SARS-CoV-2的恒河猴提出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，可用于制定标准化和 新冠肺炎稳健的RM/NHP模型(目标1)。此外，我们将在体内具体和直接地阻止类型- I型干扰素拮抗剂对SARS-CoV-2感染的RMS的干扰素应答(AIM#2) 蚂蚁)。这种干预将阐明I型干扰素在保护宿主免受严重新冠肺炎侵袭中的作用 进展和研究短期的干扰素-I和ANT治疗是否可以建立严重的和可复制的NHP 新冠肺炎模式。此外，纵向收集和尸检时收集的标本将被冷藏库 在COVTEN联合体之间共享和使用，以验证已建立的SOP以及解决 其他与新冠肺炎炎症和发病机制相关的问题。 纵向跟踪发病机制、免疫反应和病毒复制的优势，包括非常 感染后早期，并跨越多个组织，包括肺、心脏和脑，将使我们能够解决我们的 关键问题具有深度和严谨性，这在人类身上几乎是不可能实现的。这些成就 将为SARS-CoV-2致病机制提供关键见解，并将提供强大的 优先排序和加速最有希望的候选人发展的NHP模型 治疗学。这项研究将交叉验证COVTEN SOP，并建立一个健壮的模型，供 主动财团。