When infected with SARS-CoV-2, why do some people—such as smokers and older adults— have extreme respiratory and cardiovascular distress while others have no symptoms at all?

A multi-disciplinary Duke team including a virologist, pulmonologist, and a pediatrician are working to answer this question by studying a surface molecule found on the thin layer of epithelial tissue that lines the lungs, heart and most other organs in the body.

The molecule, called angiotensin-converting enzyme 2 (ACE-2), is primarily known for lowering blood pressure; however, it is also a known entry point into cells for SARS-coronaviruses. The team is investigating whether this molecule and the partners it interacts with inside the cell are expressed differently in populations who often have extreme COVID-19 symptoms.

“The hypothesis we are working on is that, in smokers, the receptor is expressed at higher levels compared to non-smokers, which would give the virus additional ‘ports of entry’ and therefore facilitate its spread from one cell to another,” said virologist Maria Blasi, PhD, assistant professor of medicine and a member of the Duke Human Vaccine Institute.

To study the receptor, the team is using a model that pulmonologist Scott Palmer, MD, professor of medicine, immunology and population health sciences, has used in the past to assess the impact of smoking and vaping on airway cells. In the lab, Palmer grows human airway epithelial cells and exposes them to tobacco smoke and flavoring agents commonly used in e-cigarettes.

For the COVID-19 project, he hands off the cells to Blasi, who infects them with SARS-CoV-2 and observes what happens in cells that have been infected with the virus and treated with smoking flavoring agents versus those that have only been infected with the virus.

“The airway epithelium is the first line of host defense, and exposures like smoking or vaping may render that epithelium injured and more vulnerable to SARS-CoV-2, both in terms of susceptibility and severity of infection once it occurs,” said Palmer. “Understanding how smoke or vaping exposure renders the epithelium vulnerable will give us insight not only in how to better treat patients with smoking or vaping exposures that then are exposed to SARS-CoV-2, but also give a broader understanding of how COVID-19 attacks and overcomes natural host defenses to cause disease,” said Palmer.

With the help of Sallie Permar, MD, PhD, professor of pediatrics, immunology, pathology and molecular genetics and microbiology, and a member of the Duke Human Vaccine Institute, the team is also examining both young and old non-human primate lung epithelial cells isolated by collaborators at the California National Primate Research Center, by infecting them with the virus to define the host factors that mediate protection from severe SARS-CoV-2 disease in children. So far, children who have tested positive for COVID-19 are typically either asymptomatic or have few symptoms.

“This work will bring together investigations of human lung epithelial cell biology, molecular virology, and the highly-relevant viral pathogenesis models in nonhuman primates, exploiting the laboratory expertise of scientists specializing in these areas who before COVID-19 had not yet collaborated,” said Permar, MD, PhD, professor of pediatrics, molecular genetics and microbiology, immunology, and pathology.

Looking forward, the researchers hope that a better understanding of the molecular mechanisms responsible for more severe disease in these high-risk populations will lead to the discovery of novel therapeutic targets for coronaviruses disease.