Lung Model Aids SARS-CoV-2 Research
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Learning more about SARS-CoV-2, the novel coronavirus behind the current COVID-19 pandemic, is a crucial part of global efforts to battle the outbreak. Understanding the virus’ biology and learning how it infects cells and spreads within tissue will help researchers on their quest to develop successful anti-viral strategies. In order to undertake these studies, scientists need an effective modeling platform, composed of the types of human cells that the virus would encounter in the body.
An in vitro model of the human lung airway epithelium developed by Newcells Biotech is currently being tested as a platform for modeling SARS-CoV-2 infection. To learn more about the model and how it could help in the fight against SARS-CoV-2, Technology Networks spoke to Dr Mike Nicholds, CEO, Newcells Biotech.
Laura Lansdowne (LL): Can you touch on the significance of the ACE2 protein in relation to the novel coronavirus (SARS-CoV-2)?
For SARS-CoV-2 and similar coronaviruses, cell entry is promoted by the virus spike protein, S. The entry receptor on host cells to which the SARS-CoV-2 S protein binds is the membrane protein angiotensin converting enzyme 2 (ACE2). ACE2 expression within different tissues has been examined by researchers and found to be expressed not only in the lungs but other tissues as well. In the lung airway, expression is polarized i.e. higher on the apical surface (air-exposed side) than deeper in the tissue. This is why our model, which is designed to mimic this polarized orientation, is potentially so useful.
LL: Can you tell us more about your hiPSC-derived upper airway model and explain how this assay could be used to discover anti-viral approaches to combat SARS-CoV-2 infection?
The model is produced by first generating a population of basal airway epithelial cells from one of our in-house iPSC cell lines. These basal cells are the population from which all other cells in the lung airway epithelium are derived, and we have developed a proprietary method to expand this population at scale. We take the basal cells and subject them to a series of growth factor and environmental conditions which in essence mimics the conditions seen in a normal developing lung. This induces the basal cells to convert and self-assemble into a model of the airway epithelium. We produce the model in 24-well plastic assay plates with the upper (apical) surface exposed to the air, as would be the case in vivo.
Anna MacDonald (AM): What makes the model well suited as a platform to study the biology of the virus? What could be learned about the virus using the model?
One of the advantages is that we can produce the model at scale from individual human iPSC cell lines, meaning that the genetic background in each of the assay plates is the same. This removes one experimental variable that would be present when you use primary cells (models produced from many different human donors) and helps to simplify the interpretation of the results. Another advantage is that we believe we can produce this model at scale from resources in-house, without needing to continually source fresh primary tissue from donors.
Using this model is a convenient platform to carry out a number of different types of study that will aid in the fight against the virus. First, you could use the model to test for agents that block the entry of the virus into the cell, and there are a number of companies advancing antibodies that do this. Second, you could screen for anti-virals that inhibit the various stages of replication that occur once the virus is inside the cell. Third, the model could facilitate research into the fundamental biology of the virus. For example, how the virus enters the cell is a complex process that is still not fully understood – it involves not only binding to ACE2, but the action of other proteins too. Additionally, while the genome of the virus has been sequenced and so we know what virally-encoded proteins are made, the function of some of these is unclear. Using our model as a standard platform would allow comparison of results from international researchers.
AM: Can you explain what a challenge experiment is and why it is important?
The “challenge experiment”, as we call it, is the next step in the proof-of-concept plan where we challenge our model with SARS-CoV-2 virus in the high containment facilities of our collaborators – who have been licensed to handle the virus. We intend to dose the model with different concentrations of the virus and follow the infection cycle over time. If successful we hope to demonstrate two key things: that our model can be infected by the virus and that it supports virus replication and shedding.
LL: Are you able to share any further details regarding planned next steps, once the protocols for the challenge experiments have been established?
If we get positive results from the challenge experiment and our initial characterization data of the model gives us optimism, we will continue to do more work to characterize the model and also look at assay outputs - for example looking at secreted cytokine profiles. We are also in initial discussions with groups that have anti-virals which they would like to test in our model.
Mike Nicholds was speaking to Laura Elizabeth Lansdowne and Anna MacDonald, Science Writers for Technology Networks.