Interferon (IFN)-? promotes monocyte-mediated lung injury during influenza pathogenesis

Influenza A Virus (IAV) triggers an exuberant host response that promotes acute lung injury. However, the determinants of the pathological host response to IAV remain incompletely understood. In the current study, we identified interferon (IFN)-?-regulated subset of monocytes, CCR2+ monocytes, as a driver of lung damage during IAV pathogenesis. IFN-? regulated the recruitment and inflammatory phenotype of CCR2+ monocytes, and CCR2 (CCR2-/-) and IFN-? (IFN-?-/-) deficient mice exhibited reduced lung inflammation, pathology, and increased resistance against bacterial co-infection by Streptococcus pneumoniae (Spn). Adoptive transfer of WT (IFN-?R1+), but not IFN-?R1 deficient (IFN-?R1-) CCR2+ monocytes, restored the wild-type (WT)-like pathological phenotype of lung damage in IAV-infected CCR2-/- mice. The CD8+ T cells were the most significant source of IFN-? in IAV-infected lungs. Collectively, our data highlight that IFN-? regulates CCR2+ monocyte-mediated lung pathology during IAV pathogenesis. Overall design: scRNAseq profiles of mock, 7 days post-viral infection