Approximately 15 to 20 million Americans who have acquired COVID-19 experience persistent symptoms lasting over 3 months (long-COVID). Respiratory symptoms of long-COVID include breathlessness, coughing, and chest pain/tightening.

A multi-institutional study led by researchers at the University of Alabama at Birmingham (UAB) and the University of North Carolina at Chapel Hill (UNC-Chapel Hill) has revealed a previously underappreciated mechanism by which SARS-CoV-2 infection contributes to long-term lung damage. The study, published in Nature Microbiology, demonstrates that SARS-CoV-2 uniquely induces the formation of foam cells—lipid-laden macrophages with pro-fibrotic and pro-thrombotic properties—in human lung tissue.

Using mouse models, non-human primates, and post-mortem human lung samples, the researchers found that SARS-CoV-2 infection significantly increases macrophage numbers and foam cell formation in the lung, unlike other coronaviruses such as SARS-CoV-1, MERS-CoV, and bat-derived strains. These foam cells express genes linked to platelet activation, collagen synthesis, and extracellular matrix remodeling, contributing to persistent lung fibrosis and thrombi formation even after viral clearance.

“This study provides evidence that foam cells are a product of SARS-CoV-2 infection and possibly active contributors to the lung damage seen in COVID-19,” said J. Victor Garcia, Ph.D., professor and chair, Charles H. McCauley Endowed Chair in the UAB Department of Microbiology. “Our findings underscore the importance of early antiviral intervention to prevent lasting pulmonary injury.”

Importantly, the study shows that early treatment with the antiviral EIDD-2801 (molnupiravir) can prevent foam cell formation and reduce fibrosis markers, suggesting a potential therapeutic strategy to mitigate long-term COVID-19 complications.

“The ability of EIDD-2801 to prevent foam cell formation and reduce fibrosis—even when administered post-infection—offers real hope for mitigating long-term lung damage in COVID-19 patients,” said Angela Wahl, Ph.D., co-senior author and associate professor in the UAB Department of Microbiology.

Foam cells were found to persist in lung tissue even after the virus was cleared, suggesting that individuals who recover from mild or moderate COVID-19 may still be at risk for lasting pulmonary damage.

“As a postdoctoral fellow, contributing to this discovery has been incredibly rewarding," added Diana Battaglia, Ph.D., co-first author and postdoctoral fellow in the Garcia/Wahl laboratory in the UAB Department of Microbiology. "Foam cells may be the missing link between acute infection and chronic lung complications."

The research team included co-first authors Claire E. Post, former graduate student, and Wenbo Yao, Ph.D., former postdoctoral fellow in the Garcia/Wahl laboratory, and Lisa Gralinski, Ph.D., assistant professor at UNC-Chapel Hill. This work was a large collaborative effort between investigators from UAB, UNC-Chapel Hill, the University of California Davis, Duke University, and the University of California San Diego.