Experimental design: SftpcCreERt2/+::Bmal1fl/fl mice (mice lacking Bmal1 in AT2 cells of the lung epithelium) and their creneg littermates were treated with tamoxifen at 6–8 weeks of age and acclimatized to reverse cycles of 12 hr LD for 2 weeks. Thereafter, they were maintained in constant darkness for 2–4 days prior to administering IAV (PR8) at CT23 and CT11 and acclimatized to reverse cycles of 12 hr LD for 2 weeks. Thereafter, they were maintained in constant darkness for 2–3 days prior to administering IAV (PR8) at CT23 and CT11. CT23 and CT11 refer to the time corresponding to ZT23 and ZT11, respectively, when animals are maintained under constant darkness conditions. (A) Survival curves (n = 16–18 in SftpcCreERt2/+::Bmal1fl/fl groups and n = 20–21 in creneg, *p=0.0014 Mantel–Cox test; pooled data from four independent experiments). (B) Percentage of body weight lost (n = 16–18 in SftpcCreERt2/+::Bmal1fl/fl groups and n = 18–20 in creneg group from three independent experiments *p<0.01 ANOVA for repeated measures). (C) Viral burden measure by hemagglutination inhibition assay (n = 5–13/group) by two-way ANOVA, p<0.0001 for time post-infection, p=0.9981 for treatment group and interaction. (D) Left: Representative micrographs of H and E stained lung sections 8 days after IAV (40 PFU) treatment of SftpcCreERt2/+::Bmal1fl/fl mice and their cre− littermates (photomicrograph bar = 100 µm). Right: Severity of lung injury quantified using an objective histopathological scoring system by a researcher blinded to study group (n = 4–8 mice/group; data as median, IQR; Wilcoxon rank sum test; **p=0.0014, CT23 vs. CT11 for Cre+ refers to SftpcCreERt2/+::Bmal1fl/fl mice vs. Cre− which refers to SftpcCreERt2neg::Bmal1fl/fl; pooled data from three independent experiments).