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

Abstract

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 defence 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‐signalling‐deficient (Ifnar1–/–) mice, to study type I IFN signalling deficiency and innate immune responses during SARS‐CoV‐2 infection. Our data show that type I IFN signaling 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 a 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 deficiency results in a dysregulated innate immune response to SARS‐CoV‐2 infection.This article is protected by copyright. All rights reserved