Risk factors for severe COVID-19 aren’t always straightforward. Respiratory illnesses such as asthma and chronic obstructive pulmonary disorder (COPD) are often exacerbated by viral infections, but not by COVID-19. Cystic fibrosis (CF), a condition marked by the overproduction of thick and sticky mucus in the lungs, has a more complicated relationship. While patients are at risk for serious breathing problems when exposed to influenza, they often fare better than others with respiratory syncytial virus and COVID-19 (1).
Earlier this year, Darrell Kotton and Finn Hawkins, stem cell biologists at Boston University, made airway basal stem cells, which can differentiate to become any of the cells found in the airway, from induced pluripotent stem cells (iPSCs), creating a new airway model to help understand why patients with CF aren’t more susceptible to severe COVID-19 (2).
“This paper highlights a new advancement in the field of stem cell derivation of lung cells,” said Amy Wong, a stem cell biologist at the Hospital for Sick Children who was not involved in this study, in an email. “It provided us an opportunity to generate these renewable sources of basal stem cells that we can then use to generate efficient models of CF in vitro to identify new therapies, for example, finding new drugs using patient derived iPSCs.”
Ruobing Wang, a clinician researcher at Boston’s Children’s Hospital, teamed up with Kotton and Hawkins to put their iPSC-derived basal stem cells (iBCs) to the test. She uses iBCs to make epithelial airway cells from CF patient cells to model CF and study how COVID-19 infection may infect CF patient airway cells differently.
Wang sees CF patients regularly and was extremely concerned for her patients in the beginning of the pandemic. She watched many people with CF suffer severe, even deadly, H1N1 infections during the virus’s infamous surge in 2009, so she asked her patients to hunker down until scientists knew more about COVID-19. As the pandemic progressed, she was surprised to see data suggesting that patients with CF were not at increased risk of infection.
Wang explained that CF is more than just a respiratory disease. Patients have diabetes, which is a definitive risk factor for severe COVID-19 infection, and dysregulated immune responses. Additionally, many CF patients receive lung transplants and take immunosuppressive drugs to prevent rejection.
“We don’t know how their airway systems react to COVID-19 in a large sense because they are so good at social distancing, and many patients are children, so we just can’t draw strong conclusions. That’s what really got me to start this project,” said Wang.
Wang has the “perfect platform” to disentangle how COVID-19 infects the airways of CF patients. She isolates blood or skin cells from CF patient volunteers, then turns them into iPSCs. From there, she differentiates the cells into iBCs, then epithelial airway cells that contain the patients’ CF-causing mutation. As a control, she corrects the mutation in the CF patient cells before she differentiates them into airway cells.
“We have a genetically matched system, which is a very clean way to answer our question,” said Wang.
Once Wang has these genetically matched airway cells, she grows them in an air liquid interface culture. Cells grow on the bottom of an open box-like plate in a small amount of liquid, allowing air movement across the open top.
“By developing this method, we did viral infections like what happens in the lung when the virus comes in through the air and infects the cell. The model worked really well. The cells were very infectable. We learned a lot about how a human lung cell responds when it's first infected,” said Kotton.
Now, Wang uses this culture system to look for differences in how COVID-19 enters the CF cells and if this relates to the observed decrease in patient susceptibility. Her results are currently preliminary and need to be validated in more cell lines, but she sees some evidence of differences between the CF and non-CF cells. She plans to pin down the mechanism behind those differences by performing RNA sequencing on the cells to document any differential expression for relevant genes.
“If we are convinced there's a difference, then the next question is what drugs should you use to treat COVID-infected cystic fibrosis patients? Should they be given the same drugs as everyone else? Should it be tailored a bit? Should we be also combining it with specific cystic fibrosis drugs that help or hurt the response to infection?” said Kotton.
References
- Peckham, D. et al. COVID-19 meets Cystic Fibrosis: for better or worse? Genes and Immunity 21, 260-262 (2020).
- Hawkins, F.J. et al. Derivation of Airway Basal Stem Cells from Human Pluripotent Stem Cells. Cell Stem Cell 28 (2021).
