Interferon-lambda accelerates viral clearance and regulates CD8+T cells immunity in a murine model of SARS-CoV-2 infection

Abstract SARS-CoV-2 remains a significant global health burden. A better understanding of the requirements for protective host immunity against SARS-CoV-2 will contribute to the development of novel therapeutic strategies to prevent disease. Type III interferon (IFN-lambda) limits SARS-CoV-2 infection in vitro and in murine models of infection. In clinical trials, IFN-lambda treatment accelerates viral clearance of SARS-CoV-2 and reduces risk of hospitalization. However, roles for IFN-lambda in regulating SARS-CoV-2 pathogenesis and protective immunity are not well understood. Infection of C57BL/6 (WT) and IFN-lambda receptor deficient mice (Ifnlr1 −/−) with mouse-adapted SARS-CoV-2 lead to increased weight loss and viral load in Ifnlr1 −/−compared to WT through day 5 post infection (pi). Global transcriptomics revealed differential regulation of proliferation and immune cell programming pathways in Ifnlr1 −/−lungs compared to WT, suggesting IFN-lambda signaling regulates protective pathways outside of canonical interferon stimulated gene responses following SARS-CoV-2 infection. Histological and flow cytometric analysis confirmed an increase in proliferation in multiple cell subsets within lungs of Ifnlr1 −/−lungs compared to WT following SARS-CoV-2 infection. Additionally, SARS-CoV-2 specific CD8 +T cells in the lungs of Ifnlr1 −/−mice are significantly reduced compared to WT on day 8 pi. Together, these studies suggest IFN-lambda signaling is required for regulation of proliferative repair pathways and CD8 +T cell immunity against SARS-CoV-2. Overall, broadening the understanding of how IFN-lambda regulates SARS-CoV-2 infection, pathogenesis, and immunity may inform its therapeutic utilization.