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