Mechanistic interrogation of the role of Type I IFN pathway in protection from SARS-CoV-2 infection in nonhuman primates

I 型 IFN 通路在非人灵长类动物免受 SARS-CoV-2 感染保护中的作用的机制探讨

• 批准号: 10597472
• 负责人: Larry S. Schlesinger
• 金额: $ 50万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-06 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597472
• 关键词: 2019-nCoV; Ablation; Acute; Address; Animals; Antibodies; Autoantibodies; Automobile Driving; COVID-19; COVID-19 therapeutics; Cells; Clinical Management; Confocal Microscopy; Cytokine Gene; Development; Disease; Evaluation; Event; Flow Cytometry; Fostering; Foundations; Friends; Funding; Health; Hereditary Disease; Immune; Immune system; Immunologics; Infection; Interferon Type I; Interferons; Liquid substance; Lung; Macaca; Macaca mulatta; Medical; Modeling; Mycobacterium tuberculosis; Nose; Oral; PET/CT scan; Pathway interactions; Persons; Phase; Plasma; Pneumonia; Post-Acute Sequelae of SARS-CoV-2 Infection; Predisposition; Proteins; Pulmonary Pathology; RNA; Reagent; Recombinants; Resolution; Resources; Reverse Transcriptase Polymerase Chain Reaction; Role; SARS-CoV-2 exposure; SARS-CoV-2 infection; Severities; Signal Transduction; Swab; Techniques; Therapeutic Intervention; Time; Tissues; United States National Institutes of Health; Vaccines; Viral; Viral Load result; Virus; Virus Diseases; Virus Replication; Work; antagonist; base; coronavirus disease; cytokine; cytokine release syndrome; effectiveness evaluation; experimental study; in vivo; inhibiting antibody; inhibitor; nasal swab; nonhuman primate; pathogen; rectal; response; severe COVID-19; therapeutic development; transcriptome sequencing; vaccine development; vaccine hesitancy; variants of concern; working group

Summary While Type I IFN responses are a critical anti-viral mechanism, there is a lack of clarity about their role in protecting against or driving severity to COVID-19. In our NHP model of SARS-CoV-2 infection, (RMs) mounted a strong Type I IFN response. Dynamic changes to these robust levels of Type I IFN cytokines correlate strongly with the increase and the decrease in lung compartment viral loads, suggesting that there is a strong early role for this signaling in the control of SARS-CoV-2 infection. Recently, the NHP Reagent Resource funded by the NIH developed a simianized version of a Type I IFN depleting antibody (anifrolumab), which functions well, and which we have validated. We therefore propose to perform mechanistic experiments where the progression of viral infection, disease parameters, and cytokine responses will be compared SARS-CoV-2 infected RMs (n=6, Group 1), with those treated with Type I IFN inhibiting antibody from NHPRR (n=6; Group 2) and those treated with recombinant IFN molecule (n=6, Group 3). We will compare viral replication, lung pathology and pneumonia and cytokine levels in the three groups of rhesus macaques. Using these experiments, we will be able to definitively address if silencing Type I IFN signaling at the time of infection result in more SARS-CoV-2 replication and progression to COVID-19.

概括 虽然 I 型干扰素反应是一种重要的抗病毒机制，但其在抗病毒过程中的作用尚不清楚。 预防或加剧 COVID-19 的严重程度。在我们的 SARS-CoV-2 感染 NHP 模型中，(RM) 安装 强烈的 I 型干扰素反应。 I 型干扰素细胞因子的这些强劲水平的动态变化密切相关 随着肺室病毒载量的增加和减少，表明有很强的早期作用 该信号在控制 SARS-CoV-2 感染中发挥作用。 最近，由 NIH 资助的 NHP 试剂资源开发了 I 型 IFN 的简化版本 消耗抗体（anifrolumab），其功能良好，并且我们已经对其进行了验证。因此我们建议 进行机械实验，其中病毒感染、疾病参数和细胞因子的进展 将比较感染 SARS-CoV-2 的 RM（n = 6，第 1 组）的反应与接受 I 型 IFN 治疗的反应 来自 NHPRR 的抑制抗体（n=6；第 2 组）和用重组 IFNα 分子治疗的抗体（n=6，第 2 组） 3）。我们将比较三组中的病毒复制、肺部病理学和肺炎以及细胞因子水平 恒河猴。使用这些实验，我们将能够明确解决是否沉默 I 型 IFN 感染时的信号传导导致更多 SARS-CoV-2 复制并进展为 COVID-19。