NON-CANONICAL MECHANISMS FOR INTERFERON-LAMBDA REGULATION OF SARS-COV-2 INFECTION

干扰素-Lambda 调节 SARS-COV-2 感染的非典型机制

• 批准号: 10574001
• 负责人: Emily Ann Hemann
• 金额: $ 22.63万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574001
• 关键词: 2019-nCoV; Adoptive Transfer; Antibody Response; Body Weight decreased; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 pandemic; COVID-19 prevention; COVID-19 therapeutics; Cell Cycle; Cell Cycle Regulation; Cell physiology; Cells; Clinical Trials; Data; Dendritic Cells; Development; Disease; Epithelial Cell Proliferation; Epithelial Cells; FOXM1 gene; Fibrosis; Generations; Genes; Goals; Histologic; Human; Immune response; Immunity; Immunologic Adjuvants; Immunologic Factors; Immunologist; In Vitro; Infection; Influenza; Influenza A virus; Interferons; Knock-out; Knockout Mice; Lung; Lymphocytic Infiltrate; Mediating; Memory; Mucous Membrane; Mus; Pathogenesis; Pathology; Pathway interactions; Process; Proliferating; Recombinant Interferon; Recombinants; Recovery; Regulation; Research; Role; SARS-CoV-2 immunity; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; SARS-CoV-2 pathogenesis; Seminal; Signal Transduction; Stains; T cell response; T-Cell Activation; Therapeutic; Therapeutic Uses; Time; Tissues; Training; Up-Regulation; Vaccines; Variant; Viral; Viral Genes; Viral Load result; Virus; Virus Diseases; Virus Replication; Work; adaptive immune response; antiviral immunity; cytokine; draining lymph node; epithelial repair; experience; experimental study; gene induction; immune activation; improved; in vivo; innovation; insight; knockout animal; mouse model; neutralizing antibody; novel; pharmacologic; post SARS-CoV-2 infection; prevent; programs; receptor; repaired; respiratory infection virus; respiratory virus; response; severe COVID-19; therapeutically effective; tissue repair

PROJECT SUMMARY As the SARS-CoV-2 pandemic continues, a better understanding of the factors that regulate broadly protective immunity is needed. Interferon-lambda (IFN-λ) mediates antiviral protection against SARS-CoV-2 without causing overt pathology and exacerbated disease. As such, recombinant IFN-λ is in clinical trials as a therapeutic for COVID-19. However, the endogenous role for IFN-λ in regulating infection and functions in preventing disease beyond antiviral programming during SARS-CoV-2 remain unknown. Our preliminary data show that mice lacking the IFN-λ receptor (Ifnlr1-/-) have increased illness and viral burden during SARS-CoV-2 infection without alteration of canonical antiviral gene induction associated with IFN. Instead, IFN-λ positively regulates the induction of CD8 T cell immunity, a cellular immune response critical to mediating protection against virus infection when neutralizing antibody responses are avoided. We further identified upregulation of cell cycle repair and proliferation genes associated with fibrosis in Ifnlr1-/- mice. This proposal will investigate these newly identified non-canonical functions of IFN-λ in regulating immunity against SARS-CoV-2 with the goal of informing therapeutic use of this cytokine.

项目概要 随着 SARS-CoV-2 大流行的继续，更好地了解调节广泛保护性的因素 干扰素-λ (IFN-λ) 可介导针对 SARS-CoV-2 的抗病毒保护，而无需免疫。 导致明显的病理学和恶化的疾病，因此，重组 IFN-λ 正在作为一种治疗方法进行临床试验。 然而，IFN-λ 在调节感染和预防疾病方面的内源性作用 SARS-CoV-2 期间的抗病毒编程之外的功能仍然未知。我们的初步数据显示，小鼠缺乏这种功能。 IFN-λ 受体 (Ifnlr1-/-) 在 SARS-CoV-2 感染期间增加了疾病和病毒负荷，而无需 相反，IFN-λ 正向调节与 IFN 相关的经典抗病毒基因诱导。 诱导 CD8 T 细胞免疫，这是一种对于介导病毒防护至关重要的细胞免疫反应 当避免中和抗体反应时，我们进一步确定了细胞周期修复的上调。 以及与 Ifnlr1-/- 小鼠纤维化相关的增殖基因。本提案将研究这些新的基因。 确定了 IFN-λ 在调节 SARS-CoV-2 免疫方面的非典型功能，目的是告知 该细胞因子的治疗用途。