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

项目摘要 随着SARS-CoV-2大流行的持续，更好地了解广泛保护性免疫的调节因素， 需要免疫力。干扰素-λ（IFN-λ）介导抗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IFN-λ作为一种治疗药物正在临床试验中， 为COVID-19。然而，IFN-λ在调节感染中的内源性作用和在预防疾病中的功能， 在SARS-CoV-2期间的抗病毒程序之外仍然未知。我们的初步数据显示， IFN-λ受体（Ifnlr 1-/-）在SARS-CoV-2感染期间增加了疾病和病毒负荷， 与IFN相关的典型抗病毒基因诱导的改变。相反，IFN-λ正向调节 诱导CD 8 T细胞免疫，这是介导抗病毒保护的关键细胞免疫应答 当中和抗体反应被避免时感染。我们进一步确定了细胞周期修复的上调 和与Ifnlr 1-/-小鼠中的纤维化相关的增殖基因。本提案将对这些新的 确定了IFN-λ在调节针对SARS-CoV-2的免疫中的非典型功能，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.