Human lung organoids as a translational bridge between molecular mechanisms and epidemiological patterns in COVID-19 susceptibility

The COVID-19 pandemic has highlighted significant variability in susceptibility and disease severity across age groups and among persons with pre-existing comorbidities. Older adults and patients with chronic conditions, such as chronic obstructive pulmonary disease (COPD), cardiovascular disease, and metabolic disorders, are especially vulnerable to severe outcomes following SARS-CoV-2 infection. Traditional experimental models, including animal models and two-dimensional (2D) cell cultures, have shown limited ability to accurately replicate human lung physiology. In contrast, human lung organoids have emerged as a promising platform for modelling human-specific cellular architecture, host-virus interactions, and disease-relevant responses. This review assesses the application of human lung organoids in modelling age- and comorbidity-related differences in susceptibility to SARS-CoV-2 infection and explores their value in connecting molecular mechanisms to epidemiological findings. Recent research demonstrates that lung organoids can reproduce key features of SARS-CoV-2 infection, such as viral replication, epithelial injury, and innate immune activation. However, direct SARS-CoV-2 studies comparing lung organoids derived from younger and older donors remain limited; age-related mechanisms are currently supported mainly by human tissue studies, immune-integrated organoids, and age-stratified respiratory epithelial models rather than definitive age-stratified lung-organoid experiments. Furthermore, lung organoids provide a flexible platform for evaluating antiviral and host-directed therapies under physiologically relevant conditions. In summary, human lung organoids are valuable mechanistic and hypothesis-testing tools that can strengthen the biological plausibility of epidemiological associations, although the translational evidence remains incomplete for age and several common systemic comorbidities. In summary, human lung organoids are valuable mechanistic and hypothesis-testing tools that can strengthen the biological plausibility of epidemiological associations, although the translational evidence remains incomplete for age and several common systemic comorbidities.