Type I interferon receptor signalling deficiency results in dysregulated innate immune responses to SARS‐CoV‐2 in mice

SARS‐CoV‐2 is a newly emerged coronavirus, causing the global pandemic of respiratory coronavirus disease (COVID‐19). The type I interferon (IFN) pathway is of particular importance for anti‐viral defense and recent studies identified that type I IFNs drive early inflammatory responses to SARS‐CoV‐2. Here, we use a mouse model of SARS‐CoV‐2 infection, facilitating viral entry by intranasal recombinant Adeno‐Associated Virus (rAAV) transduction of hACE2 in wildtype (WT) and type I IFN receptor‐1 deficient (Ifnar1–/–) mice, to study the role of type I IFN signalling and innate immune responses during SARS‐CoV‐2 infection. Our data show that type I IFN signalling is essential for inducing anti‐viral effector responses to SARS‐CoV‐2, control of virus replication, and to prevent enhanced disease. Furthermore, hACE2‐Ifnar1–/– mice had increased gene expression of the chemokine Cxcl1 and airway infiltration of neutrophils as well as reduced and delayed production of monocyte‐recruiting chemokine CCL2. hACE2‐Ifnar1–/– mice showed altered recruitment of inflammatory myeloid cells to the lung upon SARS‐CoV‐2 infection, with a shift from Ly6C+ to Ly6C– expressing cells. Together, our findings suggest that type I IFN signalling deficiency results in a dysregulated innate immune response to SARS‐CoV‐2 infection. During SARS‐CoV‐2 infection in mice, IFNAR1‐deficiency results in dysregulated innate immune responses, such as increased neutrophil recruitment to the lung and an altered monocyte population profile. Together with decreased expression of anti‐viral effector interferon‐stimulated genes Mx1, Oas1 and Viperin this results in higher viral loads and overall worsened disease phenotype.