Fig. 4: Inflammasome inhibition ameliorates inflammation and disease in infected MISTRG6-hACE2 mice.

a, Schematic of inflammasome inhibition in vivo. SARS-CoV-2-infected MISTRG6-hACE2 mice were treated with caspase-1 or NLRP3 inhibitors at 6–12 d.p.i. b, The frequencies of mNG⁺ human immune cells after inflammasome inhibition. n = 5 (control infected), n = 6 (caspase-1 inhibitor) and n = 4 (NLRP3 inhibitor) mice were examined over at least 2 experiments. Mean values are shown with data points. c, The frequencies of CXCL10⁺ or TNF⁺ human lung macrophages after inflammasome inhibition. n = 5 (control infected), n = 5 (caspase-1 inhibitor), n = 4 (NLRP3 inhibitor) mice were examined over at least 2 experiments. Mean values are shown with data points. d, Quantification of active caspase-1 in mNG⁺ human macrophages after inflammasome inhibition. n = 5 (control infected), n = 5 (caspase-1 inhibitor), n = 4 (NLRP3 inhibitor) mice examined over at least 2 experiments. Mean values are shown with data points. e, Serum human IL-18 levels after inflammasome inhibition. n = 4 (control; NLRP3), n = 5 (caspase-1) mice were examined over 2 experiments. Mean values are shown with data points. P < 0.0001 represents P = 1.00114 × 10⁻⁵. f, Human IL-1RA levels in lung homogenates after inflammasome inhibition. n = 4 mice were examined over 2 experiments. Mean values are shown with data points. g, Serum GSDMD levels after inflammasome inhibition. n = 5 (control infected) and n = 4 (caspase-1 inhibitor; NLRP3 inhibitor) mice were examined over 2 experiments. Mean values are shown with data points. h, Representative H&E staining (left) and histopathological scores (right) after inflammasome inhibition. n = 4 (control infected), n = 6 (caspase-1 inhibitor), n = 4 (NLRP3 inhibitor) independent mice over at least 2 experiments. For the box plots, the centre line shows the median value, the box limits show the 25th–75th percentiles, and the whiskers show the lowest (minimum) to the highest (maximum) value. Scale bars, 0.2 mm. i, Viral titres from the supernatants of BMDMs infected with SARS-CoV-2-mNG in vitro and treated with caspase-1 or NLRP3 inhibitors. n = 13 (control infected), n = 8 (caspase-1 inhibitor) and n = 5 (NLRP3 inhibitor) independent data points collected over 3 experiments. Mean values are shown with data points. Statistical analysis was performed using paired (b) and unpaired (c–i) two-tailed t-tests.

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