26 October 2020

‘Mini-lungs’ grown from tissue donated to Royal Papworth Hospital NHS Foundation Trust has provided a team of scientists from South Korea and the UK with important insights into how COVID-19 damages the lungs. 

Writing in the journal Cell Stem Cell, the researchers detail the mechanisms underlying SARS-CoV-2 infection and the early innate immune response in the lungs.

To date, there have been more than 40 million cases of COVID-19 and 1.13 million deaths worldwide. 

The main target tissues of SARS-CoV-2, the virus that causes COVID-19, especially in patients that develop pneumonia, appear to be alveoli – tiny air sacs in the lungs that take up the oxygen we breathe and exchange it with carbon dioxide to exhale.

To better understand how SARS-CoV-2 infects the lungs and causes disease, a team of scientists from the UK and South Korea turned to organoids – ‘mini-organs’ grown in three dimensions to mimic the behaviour of tissue and organs.

The team used tissue donated to the research tissue bank team at Royal Papworth Hospital NHS Foundation Trust - as well as Cambridge University Hospital NHS Foundation Trust and Seoul National University Hospital - to extract a type of lung cell known as human lung alveolar type 2 cells. 

Representative image of 3D human lung alveolar organoid showing alveolar stem cell marker, HTII-280 in red and SARS-CoV-2 entry protein, ACE2 in green.
(Credit: Jeonghwan Youk, Taewoo Kim, and Seon Pyo Hong)

By reprogramming these cells back to their earlier ‘stem cell’ stage, they were able to grow self-organising alveolar-like 3D structures that mimic the behaviour of key lung tissue.

Dr Joo-Hyeon Lee, co-senior author, and a 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 team infected the organoids, which had been grown from tissue donated to Royal Papworth Hospital, with a strain of SARS-CoV-2 taken from a patient in South Korea who was diagnosed with COVID-19 in January. 

They then studied how the cells responded to the virus. When the 3D models were exposed to SARS-CoV-2, the virus began to replicate rapidly:

  • Within six hours, the virus reached full cellular infection. Replication enables the virus to spread throughout the body, infecting other cells and tissue. Around the same time, the cells began to produce interferons – proteins that act as warning signals to neighbouring cells, telling them to activate their antiviral defences. 
  • After 48 hours, the interferons triggered the innate immune response – its first line of defence – and the cells started fighting back against infection.
  • Sixty hours after infection, a subset of alveolar cells began to disintegrate, leading to cell death and damage to the lung tissue.

'Our approach has allowed us to grow 'mini-lungs' and study what happens when they become infected'

Although the researchers observed changes to the lung cells within three days of infection, clinical symptoms of COVID-19 rarely occur so quickly and can sometimes take more than 10 days after exposure to appear. 

The team say there are several possible reasons for this delay before a patient displays symptoms: it may take several days from the virus first infiltrating the upper respiratory tract to it reaching the alveoli; it may also require a substantial proportion of alveolar cells to be infected; or it may need further interactions with immune cells resulting in inflammation.

Read more about the 'mini-lungs' COVID-19 research.