Humanized mice reveal a macrophage-enriched gene signature defining human lung tissue protection during SARS-CoV-2 infection. Kenney et al.
Summary of the study: The human immunological mechanisms defining the clinical outcome of SARS-CoV-2 infection remain elusive. This knowledge gap is mostly driven by the lack of appropriate experimental platforms recapitulating human immune responses in a controlled human lung environment. Here, we report a mouse model (i.e. HNFL mice) co-engrafted with human fetal lung xenografts (fLX) and a myeloid-enhanced human immune system to identify cellular and molecular correlates of lung protection during SARS-CoV-2 infection. Unlike mice solely engrafted with human fLX, HNFL mice are protected against infection, severe inflammation, and histopathological phenotypes. Lung tissue protection from infection and severe histopathology associate with macrophage infiltration and differentiation, and the upregulation of a macrophage-enriched signature composed of eleven specific genes mainly associated with the type I interferon signaling pathway. Our work highlights the HNFL model as a transformative platform to investigate, in controlled experimental setting, human myeloid immune mechanisms governing lung tissue protection during SARS-CoV-2 infection. This Mendeley dataset contains all of the Supplemental Items associated with this study. This includes the following: - Table S1. Related to Figure 1,4 and 6. Single-cell RNA sequencing gene-defining clusters and cluster annotation in naïve NRGL-LX and HNFL-LX, and in inoculated HNFL-LX (Excel file). - Table S2. Related to Figure 1 and 5. Proteomic analysis Matrix: Naive NRGL-LX vs. HNFL-LX, Naïve HNFL-LX vs. 2DPI HNFL0LX, Naïve NRGL-LX vs. 2DPI NRGL-LX (Excel file). - Table S3. Related to Figure 5. Phospho-proteomics analysis Matrix: Naïve HNFL-LX vs. 2DPI HNFL0LX, Naïve NRGL-LX vs. 2DPI NRGL-LX (Excel file). - Table S4. Related to Figure 5. List of differentially expressed genes and IPA scores from bulk RNA sequencing analysis of naïve and inoculated NRGL-LX (Excel file). - Table S5. Related to all figures. List of the mice and fetal donor ID used in this study (Excel file). - Movie S1. Related to Figure 2. Time-lapse (2DPI, 4DPI, 6DPI and 12DPI) 3D in vivo imaging of SARS-CoV-2 infection in NRGL mice (mp4 file).