Human lung organoids reveal donor-dependent variability in susceptibility to SARS-CoV-2 variants of concern

The emergence of SARS-CoV-2 variants of concern (VOC) Delta (B.1.617.2) and Omicron (B.1.1.529) raised global health concerns about increased pathogenicity. The ability of viruses to replicate in the lower respiratory tract (LRT) is often associated with severe clinical disease, making this an important site to consider when evaluating pathogenicity of SARS-CoV-2 VOCs. Distal human lung organoids (hLOs) are three-dimensional primary cell culture systems that enable the study of physiologically relevant LRT epithelium, including alveolar type II cells. Using hLOs derived from four human donors, we compared the fitness and pathogenicity of SARS-CoV-2 VOC Delta and Omicron, along with an ancestral clade B variant containing the D614G substitution in spike, and evaluated donor-dependent differences in susceptibility to infection. We observed substantial attenuation of Omicron in hLOs and demonstrated enhanced susceptibility to Omicron and D614G replication in hLOs from one donor. Transcriptomic analysis revealed that increased susceptibility to SARS-CoV-2 infection in these hLOs was associated with reduced tonic interferon signaling activity. Overall, we show that hLOs are a useful model to evaluate SARS-CoV-2 VOC fitness and pathogenicity. Additionally, we propose that hLOs may serve as a unique system to model the heterogeneity of SARS-CoV-2 pathogenesis in humans.