Heidelberg / Germany, January 11, 2021 – The development of a human-derived tissue model in the laboratory to study virus infection and disease progression in the alveolar cells of the lungs responsible for the exchange of oxygen and carbon dioxide with the blood may enable the study of possible treatments for acute respiratory distress syndrome (ARDS) Caused by SARS-CoV-2. Researchers in the Netherlands have shown that the SARS-CoV-2 virus replicates efficiently in their model resembling the human bronchial system thought to play an important role in the development of infection toward pneumonia and acute respiratory distress syndrome.
It has already been proven that in people with COVID-19 or some other respiratory virus, an alveolar infection can trigger a chain of events that leads to acute respiratory distress syndrome, restricting the transport of oxygen into the blood to dangerously low levels. There is also mounting evidence that the epithelium lining the alveoli plays a major role in the development of COVID-19. However, in vitro models to replicate disease progression in the alveoli of the human lungs have proven difficult, especially models that also allow SARS-CoV-2 infection. This has greatly limited our understanding of COVID-19.
The Dutch team has now addressed this deficiency by applying self-renewing organic models that contain stem cells capable of differentiating into related cell types to study disease processes. Organoids are small three-dimensional tissues with a diameter of approximately 2 mm derived from stem cells to reflect the complex structures of an organ, or at least to express selected aspects of it to meet a specific biomedical research goal. These organelles can then provide continuous sources of 2D tissues that more accurately simulate the geometry or cellular alignment of the structures under study.
A self-regenerating organic model of gas-transporting airways epithelium has been developed by the same team, but the alveolar epithelium has proven to be an even greater challenge so far. The Dutch team overcame this challenge and developed a two-dimensional “air front” system that included a base layer of stem cells in contact with culture media and an upper layer exposed to air as if it were in the lungs.
Multiple cultures infection was established and successfully infected by SARS-CoV-2 targeting cells similar to type II alveolar type, known as ATII-L, which was confirmed by transmission electron microscopy (TEM), surface marker stains and single cell sequences. Then the study sheds light on the sequence of events after injury.
By analyzing the messenger RNA expression, the study also determined the cellular immune response to the virus by infected cells. When cultures were treated with the antiviral signaling molecule interferon lambda early in the infection, SARS-CoV-2 replication was almost completely blocked, indicating that – at the right timing – the antiviral lambda could be an effective treatment. These results also indicate that these cultures could be useful in developing a therapeutic intervention against acute respiratory distress syndrome (ARDS) from COVID-19.
Organoid-derived bronchoscopy model for SARS-CoV-2 infection of type II alveolar-like human cells
Mart M. Lamers, Jelte van der Vaart, Kèvin Knoops, Samra Riesebosch, Tim I. Brugem, Anna Z. Mykytyn, Joep Beumer, Debby Schipper, Karel Bezstarosti, Charlotte D. Koopman, Nathalie Groen, Raimond BG Ravelli, Hans Q. Doymel, Jeroen A.A. Demers, George MGM Vergens, Marion P.J. Copmans, Mauro J. Moraro, Peter J. Peters, Hans Cleavers, Bart L Hagmans
DOI: 10.15252 / embj.2020105912
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