Timecourse of FACS sorted Ly6C+ monocytes, tissue resident alveolar macrophages (trAMs), monocyte derived alveolar macrophages (bmAMs) and epithelial cells from SARS-CoV-2 (maVie16) vs. IAV (PR8) infected mouse lungs

Respiratory viral infections caused by SARS-CoV-2 and Influenza virus pose significant public health concerns, with severe outcomes for at-risk and even healthy patients. While disease severity is often associated with dysregulated monocyte-macrophage activities in patients, emerging evidence highlights the active role of infected epithelial cells in early viral defense with subsequent implications on disease severity. We assessed the contribution of monocytes to host defense against respiratory viral infections and discovered that Ccr2-/- mice exhibited a markedly worsened outcome, increased viral load and more severe lung damage following SARS-CoV-2 infection, whereas we found similar disease severity upon Influenza A virus (IAV) infection. Both viral infections prompted early monocyte infiltration in wild-type mice, and longitudinal RNA sequencing of sorted lung monocytes and monocyte-derived macrophages in SARS-CoV-2 and IAV infection revealed transcriptionally similar yet temporally distinct gene expression patterns, including an induction of Interferon (IFN) type I and type II dependent genes. Interestingly, epithelial cell transcriptional responses differed significantly between SARS-CoV-2 and IAV infection. Our findings emphasize the significant role of epithelial cells in shaping the immune response during respiratory viral infections. The distinct interactions between epithelial cells, monocytes, and macrophages can lead to varying antiviral immune outcomes, as observed in SARS-CoV-2 and IAV infections.