Fig. 4: SARS-CoV-2 infection causes persistent, sub-pleural, and interstitial fibrosis in aged hamsters.

a Representative images showing epithelial proliferation in the left lung lobe of SARS-CoV-2-infected hamster at 6 days post infection (dpi, left) and 112 dpi (right) on hematoxylin and eosin (HE) stained sections. At 6 dpi, there is alveolar consolidation and inflammation, with prominent epithelial proliferation around a central bronchiole (arrows), with a cuboidal, airway-like morphology, typical of bronchiolization. At 112 dpi, inflammation is absent, but areas of alveolar bronchiolization persist throughout the lung (arrows). b Semi-quantitative scoring of histopathological lung lesions in mock- and SARS-CoV-2-infected hamsters. c, d Representative images showing sub-pleural and interstitial fibrosis in the left lung lobe of a SARS-CoV-2-infected hamster at 112 dpi. c Representative image of well-demarcated area of sub-pleural fibrosis on HE stained section, characterized by aggregates of mesenchymal cells and pale eosinophilic, fibrillary, extracellular matrix. Inset: same area stained with azan, demonstrating the presence of mature collagen fibers (blue staining). d Representative images of azan-stained sections showing an increased presence of mature collagen fibers (blue staining) in the thickened alveolar septa (arrows) of SARS-CoV-2-infected animals compared to mock-infected ones. e Digital quantification of azan-positive areas in relation to the whole lung tissue in mock- and SARS-CoV-2-infected hamsters. f Quantification of CD204⁺ M2-like macrophages in total lung area of mock- and SARS-CoV-2-infected hamsters. g Heatmap of normalized expression values for genes associated with a pro-fibrotic environment (Supplementary Table 1) at each dpi in mock- and SARS-CoV-2-infected hamsters. Expression values are scaled by row. Red indicates higher and blue lower relative expression levels. b, e, f Data are shown as box and whisker plots. The bounds of the box plot indicate the 25th and 75th percentiles, the bar indicates medians, and the whiskers indicate minima and maxima. Dots indicate individual values. Data from e, f was tested by two-tailed Mann–Whitney U test. A p value of ≤0.05 was chosen as the cutoff for statistical significance. N = 8 animals/group (b, e, f) or 4 animals/group (g). Source data is provided as a Source Data file.