Interferon-lambda (IFN-λ) is currently being investigated in a phase III clinical trial as a therapeutic against COVID-19. Exogenous IFN-λ restricts SARS-CoV-2 in vitro and in Balb/c and C57Bl/6 (WT) murine models of infection. However, roles of endogenously produced IFN-λ in SARS-CoV-2 pathogenesis are not currently known, and the overall mechanisms by which IFN-λ modulates the induction of protective immune responses in SARS-CoV-2 infections remains to be elucidated. We find that IFN-λ receptor deficient mice (Ifnlr1−/−) infected with mouse-adapted SARS-CoV-2 lose significantly more weight and have increased SARS-CoV-2 viral replication compared to WT through day 5 post infection. Intriguingly, Ifit3 and Ifitm3 are increased in the lungs of Ifnlr1−/− mice compared to WT following infection, despite similar IFN-α/β and IFN-λ mRNA levels, suggesting compensatory increases in type I IFN signaling are not driving the increased weight loss or ISG induction observed in Ifnlr1−/− mice. Global transcriptomics revealed induction of a suppressive immunoregulatory signature with increased IL-10 as a hallmark in Ifnlr1−/− lungs, suggesting IFN-λ is critically involved in regulating appropriate immune activation to limit SARS-CoV-2 pathogenesis. Histological analysis revealed a significant increase in CD45+ cells (but not neutrophils) in the lungs of Ifnlr1−/− mice compared to WT on day 5 post infection, and we identified increases in pathways associated with myeloid cell function and T cell activation in Ifnlr1−/− by comparative transcriptomics. Overall, broadening the understanding of how IFN-λ regulates SARS-CoV-2 infection, pathogenesis, and immunity will inform the utilization of IFN-λ as an immunotherapy and adjuvant.

Supported by NIH Award K22 AI146141 to EAH.