A research team led by Professor Young Seok Ju from the Graduate School of Medical Science and Engineering has developed a method to grow mini-lungs in the laboratory. This 3D organoid, composed of human lung alveolar type 2 (hAT2) cells derived from stem cells in the human lung, serves as a useful experimental model in exploring how SARS-CoV-2 infects alveolar cells to cause COVID-19. The research, conducted in collaboration with researchers from Cambridge University and Seoul National University Hospital, was published in the Cell Stem Cell journal on October 21.

In order to study the effects of infection in alveolar cells, the cell culture system of hAT2 cells was exposed to the SARS-CoV-2 virus, isolated from a Korean patient with COVID-19 who had previously traveled to Wuhan. Imaging analysis and single-cell transcriptome sequencing of the infected cells revealed an increased expression of genes related to interferons — signaling proteins that are part of the immune response to viruses — and to the inflammatory response. Interferon-stimulated genes (ISGs) and other genes involved in the viral sensing pathway were expressed at high levels, characteristic of the innate immune response. In the future, the team plans to integrate immune cells into the culture system to directly investigate the interaction between alveolar and immune cells.

The research team discovered that viral replication occurred in the infected cells within 1 day post infection (dpi), with interferon expression starting at 1 dpi and ISG expression at 3 dpi. A single viral particle was found to be sufficient to cause infection — which is seemingly inconsistent with the period of symptoms emerging in actual COVID-19 patients (about 10 days or more). The researchers explained that this is because the cell culture model fails to account for the large physical size of and dense cellular occupancy of the respiratory tract, as well as the virus’ interaction with the immune system.

This study is significant in the context of the ongoing pandemic because elucidating the mechanism of the virus’ pathogenesis can aid in developing treatments for infected patients — not only for COVID-19, but also potentially for other respiratory diseases. Future studies aim to explore physiological responses of potential patients to the virus with diseased or aged lungs.