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

Adverse outcomes in SARS-CoV-2 infected pregnant mice are gestational age-dependent and resolve with antiviral treatment

“…In addition to recapitulating aspects of human COVID-19 during pregnancy, our model identified reduction in pulmonary IFN- secretion after infection late in gestation and a corresponding increase in pulmonary viral titer as critical mediators of worse outcomes in late compared with early gestation. As deficits in type 1 IFN signaling have been associated with severe COVID-19 in both nonpregnant individuals (43) and mice (44), our data suggest that maternal morbidity may, in part, be due to an inability of pregnant dams to control viral replication because of a reduced type I IFN responses, particularly during late gestation. This potential mechanism of severe disease is consistent with immunological alterations of mouse and human pregnancy where the maternal immune response shifts to an anti-inflammatory profile to support the semi-allogenic fetus and diverts from anti-viral and cytotoxic activity (4).…”

“…Deficits in type 1 interferon (IFN) signaling are associated with severe COVID-19 in nonpregnant people (43) and mice (44). Pregnancy is associated with downregulation of prototypical cytolytic and anti-viral pathways, including type I IFNs, and upregulation of anti- inflammatory pathways toward mid to late gestation (45). We hypothesized that E16-infected dams would have a reduced type I IFN response after SARS-CoV-2 infection compared to E6- infected dams and nonpregnant females.…”

“…This potential mechanism of severe disease is consistent with immunological alterations of mouse and human pregnancy where the maternal immune response shifts to an anti-inflammatory profile to support the semi-allogenic fetus and diverts from anti-viral and cytotoxic activity (4). Moreover, in human pregnancy, there is a documented decline in early anti-viral effector cells and products including natural killer cells and type I IFNs (45).…”

“…Deficits in type 1 interferon (IFN) signaling are associated with severe COVID-19 in nonpregnant people (43) and mice (44). Pregnancy is associated with downregulation of prototypical cytolytic and anti-viral pathways, including type I IFNs, and upregulation of antiinflammatory pathways toward mid to late gestation (45).…”

The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication

“…IFNs play critical roles in limiting viral replication early after SCV2 infection, yet at later stages of infection and when dysregulated, they also contribute to disease 8,81,85,[99][100][101][102][103] . Our study is centered around innate factors limiting viral replication in the lung prior to the onset of adaptive immunity.…”