Influenza-induced activation of recruited alveolar macrophages during the early inflammatory phase drives lung injury and lethality

Koch, Clarissa M; Anekalla, Kishore R; Hu, Yuan-Shih; Davis, Jennifer M.; Ciesielski, Mark; Gadhvi, Gaurav; Chen, Shang-Yang; Turner, Margaret; Cheng, Yuan; Coates, Bria M; Abdala-Valencia, Hiam; Reyfman, Paul A; Misharin, Alexander V; Budinger, GR Scott; Winter, Deborah R; Ridge, Karen M

During infection with respiratory viruses, disease severity is linked to a hyperinflammatory endotype, characterized, in part, by increased levels of circulating cytokines and worse clinical outcomes. In this study, we identify gene expression patterns associated with three distinct phases (Infiltrating, Early Inflammatory, Late Inflammatory) in the influenza A virus response of recruited alveolar macrophages. In the Early Inflammatory phase, recruited macrophages begin expressing pro-inflammatory genes, driving cytokine-mediated lung damage and contributing to the morbidity observed in influenza-infected wild-type mice. In mice lacking vimentin (Vim-/-), genes associated with the Early Inflammatory phase are suppressed, while the expression of the Infiltrating Phase genes is maintained, which is associated with protection from influenza-induced injury. Using a bone-marrow chimera mouse model, we validate that Vim-/- recruited alveolar macrophages are sufficient to confer protection from influenza-induced mortality. Our results define the temporal dynamics of gene expression in recruited alveolar macrophages, which shape the host response to infection with respiratory viruses.