Interferon-γ promotes monocyte-mediated lung injury during influenza infection

Abstract

Influenza A virus (IAV) infection triggers an exuberant host response that promotes acute lung injury. However, the host response factors that promote the development of a pathologic inflammatory response to IAV remain incompletely understood. In this study, we identify an interferon-γ (IFN-γ)-regulated subset of monocytes, CCR2⁺ monocytes, as a driver of lung damage during IAV infection. IFN-γ regulates the recruitment and inflammatory phenotype of CCR2⁺ monocytes, and mice deficient in CCR2 (CCR2^-/-) or IFN-γ (IFN-γ^-/-) exhibit reduced lung inflammation, pathology, and disease severity. Adoptive transfer of wild-type (WT) (IFN-γR1^+/+) but not IFN-γR1^-/- CCR2⁺ monocytes restore the WT-like pathological phenotype of lung damage in IAV-infected CCR2^-/- mice. CD8⁺ T cells are the main source of IFN-γ in IAV-infected lungs. Collectively, our data highlight the requirement of IFN-γ signaling in the regulation of CCR2⁺ monocyte-mediated lung pathology during IAV infection.

Keywords: CCR2(+) monocyte; Streptococcus pneumoniae; acute lung injury; influenza; interferon-γ; single-cell RNA sequencing.