Fig 2: SARS-CoV-2-challenged hamster lungs faithfully recapitulate AT2 cytopathies in COVID-19. a. Schematic showing the experimental design for COVID-19 modeling in golden Syrian hamsters. Uninf, uninfected; Den3 and Anti-CoV-2 indicate SARS-CoV-2 challenged groups that received either a control mAb or the clone CC12.2 of anti-CoV-2 IgG,31 respectively. PFU, plaque-forming units. b. Heatmap showing transcripts/million (TPM)-normalized gene expression of specific genes associated with AT2 senescence (CDKN2A, TP53), damage associated transition state progenitor (DATP) arrested state (CLDN4, KRT8), ER stress (HSPA5/GRP78) and SASP-state (SERPINE1, COL1A, COL3A). c-d. Lungs harvested from the uninfected, infected, and infected but anti-CoV-2 IgG and infected but EIDD-2801 treated hamsters have been analyzed for the abundance of collagen deposition by Trichrome staining and quantified by ImageJ. Representative images are shown panel c. Scale bar = 200 µm. Results of the quantification are displayed as bar plot in D. Statistical significance was analyzed by one way ANOVA. Error bars represent S.E.M; n = 3. e-f. Lungs harvested from the uninfected, infected, and infected but anti-CoV-2 IgG groups were analyzed by IHC for the indicated proteins and quantified by ImageJ- IHC profiler. Representative images are shown panel E. Scale bar = 200 µm. Results of the quantification are displayed as violin plots in F. Statistical significance was analyzed by one way ANOVA; n = 4.

Fig 3: AT2 cytopathic features of IPF are detected in COVID-19 lung tissues and human pre-clinical organoid models of COVID-19. a. FFPE lung tissues collected during rapid autopsy of deceased COVID-19-infected subjects and histologically normal surgically resected lung tissues were analyzed by H&E staining (top) and for the expression of KRT8 (a marker of DATP67; middle) and TP53 (a marker of senescence; bottom) by IHC. Representative fields are shown on the left. Scale bar = 200 µm. Images were quantified by IHC profiler (ImageJ) and displayed as violin plots on the right. b. Violin plots display the abundance of key senescence-associated cytokines in the plasma from adults with COVID-19 and healthy volunteers. Statistical significance was analyzed by unpaired t-test. See also Supplemental Information 3-4 for patient demographics and cytokine concentrations. c-d. Schematic in C summarizes the various pre-clinical in vitro models of the human lung that were challenged with SARS-CoV-2, followed by RNA sequencing28 (top rows; blue font; D). Other independent SARS-CoV-2-challenged alveolar pneumocyte datasets are listed in grey font (D). Bubble plots in D show the ROC-AUC values (radii of circles are based on the ROC-AUC) demonstrating the direction of gene regulation (Up, red; Down, blue) for the classification of uninfected vs infected samples based on the signatures (below).