SARS-CoV-2 infection demonstrated in tissue model of the human lung

Researchers from the groups of Hans Clevers (Hubrecht Institute) and Bart Haagmans (Erasmus MC) developed a tissue model that closely resembles the human bronchioalveolar system. This system is thought to play a critical role in the progression of an infection with SARS-CoV-2 towards pneumonia and acute respiratory distress syndrome (ARDS). The new tissue model can be used to study virus infection and disease progression in human lungs. The results were published in The EMBO Journal on the 11^th of January.

An infection with SARS-CoV-2, the virus responsible for the current pandemic, can trigger the development of acute respiratory distress syndrome (ARDS), which causes widespread inflammation in the lungs. The development of a model for studying virus infection and disease progression in alveolar cells might enable the study of possible therapies for ARDS. Alveolar cells are located in the lungs and responsible for oxygen and carbon dioxide exchange with the blood. Researchers from the Hubrecht Institute and the Erasmus MC have developed such a model from human tissue in the lab. They demonstrated that their model closely resembles the human bronchioalveolar system, which is thought to play a critical role in the progression of an infection with SARS-CoV-2 towards pneumonia and ARDS.

Organoid technology

It is already established that in people infected with COVID-19 or other respiratory viruses, alveolar injury can trigger a cascade of events that leads to ARDS. In this syndrome, the transport of oxygen into the blood becomes restricted to dangerously low levels. There is also mounting evidence that the layer of alveolar cells – the alveolar epithelium – plays a major role in progression of COVID-19. However, in vitro models for replicating disease progression in the alveoli of human lungs have proven difficult to establish, especially models that are also appropriate for testing SARS-CoV-2 infection. This has greatly limited our understanding of COVID-19.

The researchers have now remedied this deficiency through the application of organoid technology. Organoids are tiny 3D tissues – typically around 1 to 2 mm in diameter – derived from stem cells and aim to resemble organ function, albeit in a simplified way. They are therefore also called mini-organs. Organoids can mirror the geometry, cellular organization and function of the structures that are under study.

Picture bronchioalveolar-like culture — Bronchioalveolar-like cell culture with alveolar cells in green and SARS-CoV-2 in red. Original image in Lamers and van der Vaart et al., EMBO Journal, 2020.

New model to study SARS-CoV-2 infection

The same team previously developed an organoid model for the epithelium of the airways. However, generating such a model for the alveolar epithelium proved more difficult. The researchers overcame this challenge and developed a 2D “air interface” system. This system comprises a bottom layer of stem cells that is in contact with the cell culture media and a top layer of stem cells that is exposed to the air, which closely resembles the organization of alveolar cells in the lungs.

Using the new model, multiple cell cultures were successfully infected with SARS-CoV-2. The study then shed light on the sequence of events following infection. The researchers identified a cellular immune response to the virus in the infected cells. When the cultures were treated with an antiviral signaling molecule – so-called interferon lambda – early in infection, SARS-CoV-2 replication was almost completely blocked. This indicates that, when timed right, interferon lambda could form an effective treatment against the virus. The results also indicate that the cell cultures could help in the development of therapeutic interventions against acute respiratory distress syndrome (ARDS) triggered by COVID-19.

Publication

An Organoid‐derived Bronchioalveolar Model for SARS‐CoV‐2 Infection of Human Alveolar‐type II‐like Cells. Mart M. Lamers*, Jelte van der Vaart*, Kèvin Knoops, Samra Riesebosch, Tim I. Breugem, Anna Z. Mykytyn, Joep Beumer, Debby Schipper, Karel Bezstarosti, Charlotte D. Koopman, Nathalie Groen, Raimond B.G. Ravelli, Hans Q. Duimel, Jeroen A.A. Demmers, Georges M.G.M. Verjans, Marion P.G. Koopmans, Mauro J. Muraro, Peter J. Peters, Hans Clevers^#, Bart L. Haagmans^#. The EMBO Journal 2020. DOI: 10.15252/embj.2020105912

* and ^#: these authors contributed equally

Hans Clevers is group leader at the Hubrecht Institute and the Princess Máxima Center for Pediatric Oncology, professor of Molecular Genetics at Utrecht University, and Oncode Investigator.

Bart Haagmans is group leader at the Erasmus MC.