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

项目总结 随着SARS-CoV-2大流行的继续，对广泛调控因素的更好理解具有保护作用 我们需要豁免权。干扰素-λ介导对SARS-CoV-2的抗病毒保护作用 导致明显的病理和恶化的疾病。因此，重组干扰素-λ作为一种治疗手段正在进行临床试验。 为了新冠肺炎。然而，干扰素-λ在调节感染中的内源性作用和在预防疾病中的作用 除了SARS-CoV-2期间的抗病毒规划外，尚不清楚。我们的初步数据显示，老鼠缺乏 干扰素-λ受体(Ifnr1-/-)在SARS-CoV-2感染期间增加了疾病和病毒负担，而不是 干扰素相关的规范抗病毒基因诱导的改变。相反，干扰素-λ积极地调节 诱导CD8 T细胞免疫，这是一种对介导病毒保护至关重要的细胞免疫反应 避免了中和抗体反应时的感染。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。这项提案将对这些新的 确定干扰素-λ在调节抗SARS-CoV-2免疫中的非规范功能，目的是告知 这种细胞因子的治疗用途。

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.