Researchers from the Quadram Institute working together with the UK Health Security Agency (UKHSA) have established a human ‘lung-on-chip’ model that recreates how SARS-CoV-2 infects lung cells, in a contained laboratory environment.
The model adapts current technology to allow cells that line the lungs in humans to be grown in a way that mimics physiological conditions. The cells are grown with one end based in a liquid, and the other is exposed to the air – and potentially the virus. The composition and flow of the liquid are controlled to reproduce that seen in the lung. The system also incorporates breathing-like stretching, ensuring different cells develop and interact as in the human lung.
In a study published in the journal Access Microbiology, the team showed how their system successfully mimics the way SARS-CoV-2 virus infects cells, triggering characteristic changes in the cells seen in human infections as well as recapitulating early immune response, and release of new virus particles.
Taken together, these features mean this is a powerful new way for scientists to study how SARS-CoV-2 infects our lungs cells in the laboratory, to guide future clinical research and help fight back against COVID.
An accurate model of the human alveolus, and the cells at the interface with the air, was much needed but developing a system to allow scientists to recreate it in the laboratory was a challenge. The standard technique of growing cells in a culture didn’t properly mimic what happens in the lung; models that better reflected the way the cells exist at the interface with air and liquid were a better mimic of the way the cells grow in alveoli. But these traditional static models don’t recreate the way the lung inflates and expands to bring in air, which in turn affects the immune response to viral infection.
To address this, Professor Nathalie Juge and Dr Tanja Šuligoj from the Quadram Institute made use of their experience in human gut tissue models to study interactions between gut cells, mucus and the microbiome. The team worked with Emulate Inc. of Boston, USA which specialises in developing microphysiological systems, commonly known as Organ-Chips. These are systems that recreate human tissues and organs on ‘chips’ to support a range of laboratory-based studies, reducing the need for animal studies and potentially speeding up research into new drugs and treatments.
The Quadram team adapted the Alveolus Lung Chip that uses a combination of human alveoli lining cells and lung microvascular endothelial cells, to better reflect the way these cells form in the lung. These cells were connected to a laboratory simulation of the fluid that flows through the lung. Once the cells were established, an airflow was introduced alongside mechanical flexing of the chips to copy the inflation and deflation of alveoli during breathing.
The team worked with Dr Simon Funnell and colleagues from UKHSA to assess the suitability of the system for the study of SARS-CoV-2 infection in the Quadram Institute’s containment Level 3 (CL3) facility.
There was clear evidence of virus replication in the cells in all the chips tested, with a high level of the virus detectable a day after infection and lasting until day three. This is comparable with the timeline of virus shedding in COVID-19 patients. Within two or three days, changes to the cells were apparent that matched those seen in other infections into the effects of COVID on mammalian lung cells as well as early innate immune responses observed in naturally acquired SARS-CoV-2 infection in humans.
UKHSA is continuing to develop this model to characterise virus infections with Coronaviruses that cause more severe disease intending to develop a human-relevant platform to assess new drugs and treatments against past, current and future coronavirus threats such as Disease X.
The work was supported by the US Food and Drug Administration and the Biotechnology and Biological Sciences Research Council (BBSRC), part of UKRI. The image above shows changes triggered by SARS-CoV-2 infection in lung-on-chip alveoli cells.
- Šuligoj T, Coombes NS, Booth C, et al. Modelling SARS-CoV-2 infection in a human alveolus microphysiological system. Access Microbiology. 2024 Sep 11;6(9):1-8. doi:10.1099/acmi.0.000814.v3