AAV-hACE2 mice infected with SARS-CoV-2 exhibit type I IFN-dependent immune cell infiltration. C57BL/6J (WT), IFNAR knockout, and IRF3/7 double knockout mice were transduced intratracheally with an AAV encoding hACE2 (AAV-hACE2) and infected with SARS-CoV-2 2 wk later. (a) Viral titers in the lungs of mice were measured using quantitative PCR against SARS-CoV-2.(b) Lung homogenates titered on VeroE6 cells (control and WT were from the same experiment as Fig. 1; IFNAR^−/− values from three independent experiments, n = 6 at 2, 4, and 7 DPI, and n = 4 at 14 DPI; IRF3/7^−/− values from two independent experiments, n = 5 at 2 and 7 DPI, andn = 4 at 4 and 14 DPI). (c) Heat map of top 100 up-regulated genes in SARS-CoV-2–infected C57BL/6J (WT) mice transduced with AAV-hACE2 versus SARS-CoV-2–infected AAV-GFP–transduced mice. Relative expression of these genes in noninfected/nontransduced mice and IFNAR^−/− and IRF3/7^−/− AAV-hACE2–transduced and SARS-CoV-2–infected mice. (d–i) At 2 DPI, lungs of mice were made into single-cell suspensions for flow cytometry (WT [light gray] nontransduced, noninfected values from single experiment, n = 2; WT [dark gray] AAV-hACE2 and not infected values from two independent experiments, n = 4; WT [blue] AAV-hACE2 and infected values from two independent experiments, n = 4; IFNAR^−/− values from three independent experiments, n = 6; and IRF3/7^−/− values from two independent experiments, n = 5). P values were calculated by one-way ANOVA with Tukey’s multiple comparison test. *, P < 0.05; **, P < 0.01; ***, P < 0.005; ****, P < 0.001. ns, not significant.