An international team of researchers led by a group at Rockefeller University has launched a project to determine if inherent genetic disorders can lead to life-threatening COVID-19 in previously healthy younger patients.

The group believes that the project will identify genetic pathways involved in COVID-19 development in patients who get severely ill and lead to new preventive and therapeutic strategies.

Howard Hughes Medical Institute investigator Jean-Laurent Casanova, a professor at Rockefeller, explained that inborn errors of immunity or IEIs are genetic variations that make someone more vulnerable to one or more pathogens such as the coronavirus. His team has identified single-gene mutations that compromise the immunity of normally healthy individuals and lead to severe infectious disease caused by bacterial, fungal and viral infections.

"When the outbreak of the (novel coronavirus) disease started, it seemed natural to test the same idea in the context of the emerging COVID-19 pandemic," Casanova said.

While his group at Rockefeller is spearheading the consortium, Casanova highlighted that Helen Su and Luigi Notarangelo, researchers at the National Institutes of Health, and Laurent Abel, a researcher at Necker-Enfants Malades Hospital in Paris, are also leading the investigation at their respective institutions.

While the initiative is currently funded by an undisclosed amount from the Howard Hughes Medical Institute, Casanova plans to submit grant applications to the NIH and hopes to be eventually funded by additional public agencies or private foundations.

Casanova's team will follow three major phases as part of the project to identify genetic errors that cause younger patients without other risk factors to be vulnerable to severe COVID-19.

The group is recruiting 500 otherwise healthy young patients with severe COVID-19 worldwide, as well as their family members when possible. Casanova noted that the consortium has enrolled 50 to 100 patients since starting the first phase of the project in January.

The patient cohorts will consist of children and adults less than 50 years old who have no serious pre-existing illnesses, including diabetes, heart disease or lung diseases. These patients must also have been diagnosed with COVID-19 using polymerase chain reaction methods and admitted to an intensive-care unit.

After the sample collection phase, which Casanova aims to complete within three to four months, the team will search for candidate disease-causing variants in protein-coding genes using whole-exome sequencing on genomic DNA extracted from patients' blood samples.

The researchers will then run functional studies to characterize the candidate variants further, as well as analyze immune cells from corresponding COVID-19 patients.

"Once we've selected the mutation, depending on the gene, we may require another blood sample to test leukocytes or generate other cell types from stem cells for functional studies," Casanova explained. "For example, the [problem] may not necessarily be a defect of leukocytes, but an issue of pulmonary epithelial cells."

By analyzing the immune function of cells from COVID-19 patients, Casanova's team will try to identify genetic lesions and markers of immunity that cause illness in some patients when exposed to the virus.

While the group is currently in the patient recruitment and data collection phase, Casanova anticipates seeing similarities between COVID-19 and other flu types.

"We predict, for example, that the IEI underlying severe influenza pneumonitis would also make someone prone to the coronavirus disease, because they're both RNA viruses infecting the lungs," Casanova said. "In the long run, we want to prove or disprove the idea that life-threatening diseases in the course of primary infections in previously healthy individuals is genetic."

In addition, Casanova believes the functional studies may help develop new strategies to prevent and treat COVID-19. For example, he noted that if a variant impairs the production of a protein such as interferon alpha — which is normally produced by the body in response to viral infections — then giving interferon alpha as treatment could prevent or treat the viral disease.

This story first appeared in our sister publication, Genomeweb.



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