| Summary: | 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 <i>hACE2</i> in wildtype (WT) and type I IFN receptor-1 deficient (<i>Ifnar1<sup>–/–</sup></i>) 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, <i>hACE2-Ifnar1<sup>–/–</sup></i> mice had increased gene expression of the chemokine <i>Cxcl1</i> and airway infiltration of neutrophils as well as reduced and delayed production of monocyte-recruiting chemokine CCL2. <i>hACE2-Ifnar1<sup>–/–</sup></i> mice showed altered recruitment of inflammatory myeloid cells to the lung upon SARS-CoV-2 infection, with a shift from Ly6C<sup>+</sup> to Ly6C<sup>–</sup> expressing cells. Together, our findings suggest that type I IFN signalling deficiency results in a dysregulated innate immune response to SARS-CoV-2 infection.
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