SARS-CoV-2 infection demonstrated in a human lung bronchioalveolar tissue model

It is already established that in people infected with COVID-19 or some other respiratory viruses, alveolar injury can trigger a cascade of events that leads to ARDS, restricting 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 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 permissive to SARS-CoV-2 infection. This has greatly limited our understanding of COVID-19.

The Dutch team has now remedied this deficiency through application of self-renewing organoid models containing stem cells capable of differentiating into relevant cell types for study of disease processes. Organoids are tiny 3D tissues typically around 2 mm in diameter across derived from stem cells to mirror the complex structures of an organ, or at least to express selected aspects of it to meet a given biomedical research objective. Such organoids can then provide continuous sources of 2D tissues that mimic more accurately the geometry or cellular alignment of the structures under study.

A self-renewing organoid model for the epithelium of the airways conducting the gases, has already been developed by the same team, but the alveolar epithelium has proven a greater challenge to generate so far. The Dutch team has overcome this challenge and developed a 2D "air interface" system comprising a basal layer of stem cells in contact with the culture media and a top layer exposed to the air just as it would be in the lungs.

Multiple cultures were generated and infected successfully by SARS-CoV-2 targeting primarily alveolar type-II-like cells, known as ATII-L, confirmed by Transmission Electron Microscopy (TEM), surface marker stainings and single-cell sequencing. The study then shed light on the sequence of events following infection.

The study also identified through messenger RNA expression analysis a cellular immune response to the virus by infected cells. When the cultures were treated with the antiviral signaling molecule interferon lambda early in infection, SARS-CoV-2 replication was almost completely blocked, indicating that -- when timed right -- interferon lambda could be an effective treatment. These results also indicate that these cultures could be helpful for the development of a therapeutic intervention against acute respiratory distress syndrome (ARDS) from COVID-19.