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

Influenza A virus (IAV) infection significantly contributes to global mortality each year. Previous studies have shown that monocyte-derived alveolar macrophages recruited to the lung drive injury during influenza infection. However, the exact timing and mechanism of macrophage-driven lung damage is unknown. Here, we define three distinct patterns of gene expression in recruited macrophages over the first six days post-IAV infection in mice. Additionally, we demonstrate that mice infected with IAV exhibit decreased mortality, which was associated with a temporally altered transcriptional response in recruited macrophages. During the early inflammatory phase of IAV response, macrophages were characterized by a protective shift in macrophage activation. Furthermore, using a bone-marrow chimera mouse model, we demonstrate that vimentin deficiency in recruited macrophages is sufficient to confer protection from IAV-induced mortality. Taken together, our findings provide new insight into the temporal dynamics of macrophage function in response to IAV infection.