Extended Data Fig. 1: Targeting viral replication and the downstream interferon response attenuates the hyperactive immune/inflammatory response (matched to figure 1).

a. Representative gating strategy of human immune cells in the lungs of SARS-CoV-2 infected MISTRG6-hACE2 mice. Cells isolated from lungs or bronchioalveolar lavage (BAL) were stained with antibodies against human CD45, HLA-DR, CD68, CD16, CD14, CD206, CD86, CD11B, CD11C, CD123, CD3, and mouse CD45. Cell numbers were calculated using counting beads. b. Human immune cells (numbers) in BAL (14 d.p.i.) or lungs (14 and 28 d.p.i.) of SARS-CoV-2 infected MISTRG6-hACE2 mice treated with dexamethasone (Dex), Remdesivir (RDV), anti-IFNAR2 or a combined therapy of Remdesivir (RDV) and anti-IFNAR2. 14 d.p.i., BAL: CTRL-infected n = 5; Dex, RDV, anti-IFNAR2 n = 3; anti-IFNAR2+RDV n = 4 biologically independent mice examined over 2 independent experiments. 14 d.p.i., Lung: CTRL-infected n = 7; Dex, RDV, anti-IFNAR2, anti-IFNAR2+RDV n = 4 biologically independent mice examined over 3 independent experiments. 28 d.p.i., Lung: CTRL infected n = 5, Dex n = 4, RDV n = 3, anti-IFNAR2 n = 3, anti-IFNAR2+RDV n = 6 biologically independent mice examined over 3 independent experiments. Means with individual datapoints plotted. Unpaired, two-tailed t-test. P < 0.0001 = 8.19x10⁻⁵. c. Representative flow cytometry plots and frequencies of alveolar macrophages (AMs) (middle: hCD206^hihCD86⁺hCD68⁺) or inflammatory macrophages (bottom: hCD206^lo/-hCD86⁺hCD68⁺) in 14 d.p.i. or 28 d.p.i. lungs of treated or untreated MISTRG6-hACE2 mice. 14 d.p.i.: CTRL infected n = 5, Dex n = 4, RDV n = 4, anti-IFNAR2 n = 4, anti-IFNAR2+RDV n = 4 biologically independent mice examined over at least 2 independent experiments. 28 d.p.i.: CTRL infected n = 5, Dex n = 4, RDV n = 3, anti-IFNAR2 n = 3, anti-IFNAR2+RDV n = 6 biologically independent mice examined over 3 independent experiments. Means with individual datapoints. Unpaired, two-tailed t-test. P < 0.0001 = 4.67x10⁻⁵. d. Frequencies (left) and numbers (right) of lung pDCs at 14 d.p.i. CTRL-infected n = 6, Dex n = 4, RDV, anti-IFNAR2 n = 3, anti-IFNAR2+RDV n = 6 mice examined over at least 2 experiments. Means with datapoints. Unpaired, two-tailed t-test. P < 0.0001 = 7.29x10⁻⁵. e IFNA transcript levels measured by qPCR in treated or control untreated MISTRG6-hACE2 mice infected with SARS-CoV-2: Uninfected n = 5; CTRL infected: 4 d.p.i. n = 8, 14 d.p.i. n  = 9, 28 d.p.i. n = 6; Dex: 14 d.p.i. n = 4, 28 d.p.i. n= 4; RDV 14 and 28 d.p.i. n = 3; anti-IFNAR2 14 and 28 d.p.i. n = 3; anti-IFNAR2+ Remdesivir 14 and 28 d.p.i. n = 4 biologically independent mice examined over at least 2 independent experiments. Normalized to HPRT1. Violin plots with individual datapoints. Unpaired, two-tailed t test. f. Representative histograms and frequencies of HLA-DR⁺ activated T cells in treated or control mice. 14 d.p.i.: CTRL-infected n = 5, Dex, RDV, anti-IFNAR2, anti-IFNAR2+RDV n = 4; 28 d.p.i.: CTRL infected, Dex, anti-IFNAR2+RDV n = 4, RDV, anti-IFNAR2 n = 3 biologically independent mice examined over 3 independent experiments. Means with datapoints. Unpaired, two-tailed t-test. Some of the data associated with dexamethasone therapy used here as a control have been reported¹⁹.

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