Research Examines CF Patients’ Susceptibility to COVID-19
Researchers have developed a patient-derived model of cystic fibrosis (CF) to better understand whether these patients are more susceptible to COVID-19 infection and its associated serious complications.
The project is being led by Ruobing “Ruby” Wang, MD, who cares for CF patients in the division of pulmonary medicine at Boston Children’s Hospital and is an assistant professor of pediatrics at Harvard Medical School.
While clinical data available to date suggests that CF patients may not be more susceptible to the SARS-CoV-2 virus, which causes COVID-19, and that such infection may not worsen their chronic condition, Wang believes there may be more than meets the eye.
“Because the CF community has been so effective at social distancing, there is a lack of information on how they respond to SARS-CoV-2,” Wang said in a press release.
Given CF patients’ higher susceptibility to bacterial and viral lung infections and the fact that the H1N1 swine flu virus causes serious disease in some people with CF, these patients may have different susceptibility to COVID-19, a dysregulated immune response, or both, Wang noted.
Now, Wang and her team intend to clarify how people with CF become infected and how they respond to the SARS-CoV-2 virus by using a patient-derived, airway model of CF. The work is being supported by a grant from the Cystic Fibrosis Foundation (CFF).
The new model was based on a previous airway model developed by Wang’s collaborators at Boston University’s Center for Regenerative Medicine, and was created using induced pluripotent stem cells (iPSCs) of several of her CF patients.
iPSCs are generated from fully matured cells (in this case, blood cells) that are reprogrammed back to a stem cell-like state, where they can give rise to almost every type of human cell. As such, they can be genetically modified to carry known disease-causing mutations or derived directly from patients to be used as cellular models that mimic the disease’s genetic and clinical diversity.
The new CF model contains all the major airway cell types and reproduces CF’s hallmark defect in fluid transport, allowing researchers to evaluate CF airway cells’ responses to the virus in a lab dish.
“To our knowledge, this is the first time an airway derived from [iPSCs] is being used to model the effects of SARS-CoV-2,” Wang said.
Notably, to pinpoint the role of CFTR — the missing or dysfunctional protein in CF due to mutations in the CFTR gene — in cells’ responses to COVID-19, the team created a similar model in which the disease-causative genetic defect was corrected through a gene-editing tool called CRISPR-Cas9.
“We corrected the CF mutation, but otherwise, the cells come from the same patient with the same genetic background,” Wang said, noting “this ensures that any observed difference in response to the virus is due to the CF defect.”
“This provided us with perfectly matched control samples to investigate the role of CFTR in health and disease, including responses to COVID-19 infection,” she added.
For safety reasons, Wang’s team is conducting the work at Boston University’s National Emerging Infectious Disease Laboratories Biosafety Level 3 facility.
So far, the researchers have shown that the new CF airway model can be infected by SARS-CoV-2 and that it may be used to assess responses to antiviral medications. As such, the team believes the model also may prove useful to test a particular patient’s response to antiviral therapy and thereby determine the best treatment for that particular patient, contributing to personalized medicine.
The researchers now hope to compare responses not only to the virus, but to antiviral treatments, between the CF model and the genetically corrected model.
“Information from these studies may generate useful insights to guide therapy for CF patients during the COVID-19 pandemic,” Wang said.
In addition, this type of model has the potential to be used for testing airway cells’ responses to other viruses, bacteria, or toxins. These cells may be derived from CF patients as in this model, or from people with other lung or immune conditions that may make them more susceptible to COVID-19 infection or its serious complications.