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Cambridge University Science Magazine
Central to the fight against the COVID-19 pandemic is our understanding of how the virus, SARS-CoV-2, manages to wreak such havoc on the lungs. “Mini-lungs”, grown from donated human tissues, have now been developed to shine a light on the earliest stages of SARS-CoV-2 infection, allowing us to better understand COVID-19's pathogenesis. In time, this data could be used develop life-saving treatments.

A team of scientists from the UK and South Korea generated lung organoids to investigate the infection response to SARS-CoV-2. In vivo, the virus infects human lung alveolar type 2 (hAT2) cells. Alveoli are small air sacs in the lungs, where oxygen uptake occurs, and viral infection of alveolar epithelial cells destroys these cells. This results in alveolar collapse, reduced oxygen levels in the blood, and pneumonia and lung fibrosis.

Until now, no in vitro model of hAT2 cells existed to study the infectious process in detail. Using lung tissue donated to tissue banks at the Royal Papworth Hospital, Addenbrooke’s Hospital, and Seoul National University Hospital, hAT2 cells were extracted. These cells were subsequently reprogrammed to a “stem cell”-like identity and used to grow three-dimensional “mini-lungs”, which can mimic the behaviour of normal human lung tissue.

Speaking on their findings, Dr. Joo-Hyeon Lee, co-senior author and Group Leader at the Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, said, “We still know surprisingly little about how SARS-CoV-2 infects the lungs and causes disease. Our approach has allowed us to grow 3D models of key lung tissue – in a sense, ‘mini-lungs’ – in the lab and study what happens when they become infected.”

The study found that upon infection of the lung organoids with a strain of SARS-CoV-2 taken from a patient in South Korea, the virus rapidly replicated and the expression of interferon-associated and pro-inflammatory genes was increased. Just six hours after infection, all cells in the organoid were infected with the virus. Soon after, interferons triggered the innate immune response, and the cells began to fight back against the infection. However, the virus overcame these defences, and just sixty hours after infection, the alveolar cells began to undergo cell death, damaging the lung tissue.

In patients, clinical symptoms of COVID-19 can occur >10 days after viral exposure. This delay in symptomatic infection in vivo may be due to the time taken for the virus to reach the alveolar cells, the proportion of infected cells required for symptoms to manifest, or other interactions with immune cells absent from the organoid model.

“Based on our model we can tackle many unanswered key questions, such as understanding genetic susceptibility to SARS-CoV-2, assessing relative infectivity of viral mutants, and revealing the damage processes of the virus in human alveolar cells,” said Dr Young Seok Ju, co-senior author, and an Associate Professor at Korea Advanced Institute of Science and Technology. “Most importantly, it provides the opportunity to develop and screen potential therapeutic agents against SARS-CoV-2 infection.”

In particular, the group of scientists hope to use their technique to examine what makes individuals experience especially severe cases of COVID-19, and create 3D models from cells of those who are most vulnerable to infection, such as those with pre-existing conditions and the elderly.

Publication: Youk, J., Kim, T., Evans, K. et al., Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2. (2020)

Leia Judge is a PhD student in Physiology, Development and Neuroscience, and President of BlueSci