Fig. 3. Exuberant innate response by STAT2 drives SARS-CoV-2-induced lung pathology in hamsters.

WT (blue), STAT2^−/− (red), and IL28R-a^−/− (purple) hamster strains were inoculated intranasally with 2 × 10⁵ TCID₅₀ of passage 4 (circles, n = 3) or 2 × 10⁶ of passage 6 (squares, n = 4) SARS-CoV-2. On day 4 p.i., lungs and blood were collected to score for lung damage and determine gene expression levels. a Cumulative lung pathology scores for signs of damage. Lungs were stained with H&E and scored for signs of inflammation, bronchopneumonia, edema, apoptotic bodies, and necrotizing bronchiolitis (n = 7 for each genotype). b Matched comparison between infectious viral load in the lung (left Y-axis) (values from Fig. 2c) and histopathological scores (right Y-axis) (values used in a). Lines indicate matched samples (n = 7 for each genotype). c–e Micro-CT to score for signs of damage in infected (P6 SARS-CoV-2) WT (n = 4), STAT2^−/− (n = 4), and IL28R-a^−/− (n = 3) hamster lungs. c Representative transversal micro-CT images. Yellow arrows indicate examples of pulmonary infiltrates seen as consolidation of lung parenchyma. d Five transverse cross-sections at different positions in the lung were selected for each animal and scored to quantify lung consolidations. e Quantification of the micro-CT-derived non-aerated lung volume biomarker, reflecting the volume of consolidations in the lungs. The data shown are mean ± SEM and lines indicate healthy animals (n = 3) (d, e). f, g Heat map or individual expression profiles showing differential expression of selected antiviral, pro-inflammatory, and cytokine genes in the lungs after SARS-CoV-2 infection (n = 7 per group) relative to non-infected genotype matched controls (WT (n = 7), STAT2^−/− (n = 3), and IL28R-a^−/− (n = 3)). RNA levels were determined by RT-qPCR on lung extracts, normalized for β-actin mRNA levels, and fold changes over the median of uninfected controls were calculated using the 2^(−ΔΔCq) method. Only for IFN-λ, where all uninfected control animals had undetectable RNA levels, fold changes were calculated over the lowest detectable value. Data presented as fold change (f) or log₂ fold change over non-infected control (g) Bars represent median ± IQR. h Correlation between histopathological scores (derived from Fig. 3a) and natural log-normalized gene expression levels (derived from Fig. 3f, g and Supplementary Fig. 9) in uninfected and infected animals. Non-infected animals are indicated by triangles. i A spider-web plot showing lung pathology scores (CT lung score, non-aerated lung volume, bronchopneumonia, and inflammation), cumulative gene expression level scores, and infectious virus levels normalized to SARS-CoV-2-infected WT hamsters. Statistical significance between genotypes was calculated by Kruskal–Wallis with two-sided Dunn’s post hoc test (d, e, g) and Spearman correlation (h). P values: **P = 0.0082 and **P = 0.0025 (left to right in g).