Single-cell and spatial transcriptomics from healthy and influenza-infected mice

Severe respiratory infections, including those caused by influenza viruses, can result in acute respiratory distress syndrome. To date, there are no effective pharmacological therapeutics that have been shown to improve outcomes for patients with acute respiratory distress syndrome, such that treatment strategies are supportive, involving mechanical ventilation and control of fluid intake. Although the host inflammatory response is required to limit the spread of and eventually clear the pathogen, immunopathology is also known to be a major contributor to tissue damage. In this study, we demonstrate that respiratory viral infection induces distinct fibroblast differentiation states, which we term ECM-synthesizing, damage-responsive, and interferon-responsive. We provide evidence that the exuberant activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing matrix remodeling enzymes, in particular the matrix protease ADAMTS-4, and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. All spatial transcriptomics data in this experiment was collected with 10x Genomics Visium slide serial# V19S25-036. Spatial images are available at https://trace.ncbi.nlm.nih.gov/Traces/sra/?study=SRP254210