LY6E is a pan-coronavirus restriction factor in the respiratory tract

LY6E is an antiviral restriction factor that inhibits coronavirus spike-mediated fusion, but the cell types in vivo that require LY6E for protection from respiratory coronavirus infection are unknown. Here, we used a panel of seven conditional Ly6e knockout mice to define which Ly6e-expressing cells confer control of airway infection by murine coronavirus and SARS-CoV-2. Loss of Ly6e in Lyz2-expressing cells, radioresistant Vav1-expressing cells, and non-hematopoietic cells increased susceptibility to murine coronavirus. Global conditional loss of Ly6e expression resulted in clinical disease and higher viral burden after SARS-CoV-2 infection, but little evidence of immunopathology. We show that Ly6e expression protected secretory club and ciliated cells from SARS-CoV-2 infection and prevented virus-induced loss of an epithelial cell transcriptomic signature in the lung. Our study demonstrates that lineage confined rather than broad expression of Ly6e sufficiently confers resistance to disease caused by murine and human coronaviruses. RNA from homogenized lungs was prepared from 6 uninfected wildtype mice (homozygous or heterozygous for Ly6e-flox), 4 uninfected Ly6e KO mice, 7 SARS-CoV-2 infected wildtype mice, and 7 SARS-CoV-2 infected Ly6e KO mice. Lungs were harvested from SARS-CoV-2 infected mice 3 days after intranasal inoculation.