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Organoid study by University of Cambridge and South Korean scientists reveals how Covid-19 damages lungs and leads to cell death

New insights into how Covid-19 damages the lungs have been revealed by researchers using lung organoids.

These miniature versions of the human lung were grown in the laboratory using tissue donated to hospitals in Cambridge and South Korea.

Representative image of three-dimensional human lung alveolar organoid showing alveolar stem cell marker, HTII-280 (red) and SARS-CoV-2 entry protein, ACE2 (green). Picture: Jeonghwan Youk, Taewoo Kim and Seon Pyo Hong
Representative image of three-dimensional human lung alveolar organoid showing alveolar stem cell marker, HTII-280 (red) and SARS-CoV-2 entry protein, ACE2 (green). Picture: Jeonghwan Youk, Taewoo Kim and Seon Pyo Hong

Then the researchers infected them with a strain of the virus taken from a patient in South Korea diagnosed with Covid-19 on January 26, 2020, after traveling to Wuhan, China.

Using both fluorescence imaging and single cell genetic analysis, they managed to study how the cells responded to the SARS-CoV-2 virus.

Dr Joo-Hyeon Lee, co-senior author and a group leader at the Wellcome-MRC Cambridge Stem Cell Institute at the 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 primary tissues affected by SARS-CoV-2 - especially in patients that develop pneumonia - are the alveoli, the tiny air sacs in the lungs that take up oxygen and exchange it with carbon dioxide to exhale.

To understand the impact, the team of scientists used tissue donated to tissue banks at the Royal Papworth Hospital and Addenbrooke’s Hospital in Cambridge and Seoul National University Hospital

Having extracted human lung alveolar type 2 cells, they reprogrammed them back to their earlier stem cell stage. They were then able to grow self-organising alveolar-like 3D structures that mimic the behaviour of key lung tissue.

The virus replicated rapidly once the 3D models were exposed to it - the process that enables the virus to spread through the body and infect other cells and tissues.

The researchers saw:

  • After six hours - full cellular infection was reached and at about the same time, the cells began to produce interferons. These proteins act as warning signals to neighbouring cells to activate their anti-viral defences;
  • After 48 horus - the interferons triggered the innate immune response and the cells started fighting back against the infection;
  • After 60 hours - a subset of alveolar cells began to disintegrate, leading to cell death and damage to the lung tissue.

Clinical symptoms of Covid-19 rarely occur this rapidly in people and can even take more than 10 days after exposure to appear.

There may be a number of reasons for this.

The researchers’ paper, published in Cell Stem Cell, explains: “Viral infiltration from the upper respiratory tract to terminal alveoli may take several days; a substantial proportion of alveolar cells may need to be infected before displaying symptoms; or, further interactions with immune cells resulting in inflammation may be necessary for developing symptoms.”

The technique has multiple uses.

Dr Young Seok Ju, co-senior author and an associate professor at Korea Advanced Institute of Science and Technology (KAIST), said: “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.

“Most importantly, it provides the opportunity to develop and screen potential therapeutic agents against SARS-CoV-2 infection.”

Dr Lee added: “We hope to use our technique to grow these 3D models from cells of patients who are particularly vulnerable to infection, such as the elderly or people with diseased lungs, and find out what happens to their tissue.”

The research was a collaboration involving scientists from the University of Cambridge, KAIST, Korea National Institute of Health, Institute for Basic Science, Seoul National University Hospital and GENOME INSIGHT Inc in South Korea.

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