Researchers at the University of Virginia (UVA) School of Medicine have uncovered a potential path to treatment for persistent COVID-19 symptoms impacting the lungs. The work, published in Science in an article titled, “Macrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae,” identifies how the viral infection damages macrophages and suggests treatment with a pre-existing FDA-approved drug.
“Our discovery is important because it not only explains why some people continue to have breathing problems long after their initial illness but also points us toward a potential treatment to help them recover,” said senior researcher Jie Sun, PhD, of Carter Center for Immunology Research and the Division of Infectious Diseases and International Health at UVA.
Infection of the respiratory system by diseases like COVID-19 and flu causes damage to the epithelium. During the healing process, regenerative cells are typically kept in check by macrophages, as excessive presence of progenitor cells can lead to pathological tissue remodeling or fibrosis. Macrophages are critical for this process, directing tissue repair through the function of peroxisomes, which reduce inflammation and promote tissue regeneration by digesting lipids and toxins.
“COVID-19 can leave the lungs unable to heal properly by damaging these tiny structures inside our cells,” Sun said.
The team determined that COVID-19 and flu infection damages peroxisomes, thus reducing recovery and prolonging symptoms. In effect, the virus not only causes acute damage but also impairs the body’s ability to heal itself, leading to long-term complications.
“We are collaborating with scientists and physicians at UVA and other institutions to understand the exact function of this understudied organelle in long COVID and other chronic lung diseases such as interstitial lung disease [ILD],” Sun said.
Using a mouse model, the researchers examined changes to macrophage morphology following infection with SARS-COV-2. Mice with severe infection had increased interferon signaling, which both prevented the creation of peroxisomes and accelerated their degradation. This dysfunction resulted in disruption of the macrophage’s ability to function properly, leading to persistent inflammation and lung scarring, key contributors to long COVID symptoms.
In human patients with post-acute sequelae, or long COVID, researchers identified a parallel phenotype of chronic peroxisome impairment as seen in mice. This suggests a similar mechanism in mouse models and humans.
The team further identified a treatment for these chronic symptoms by restoring peroxisome function. Treatment of mouse models with sodium 4-phenylbutyrate (4-PBA) “restored peroxisome function in macrophages, mitigated lung inflammation and fibrosis, and enhanced alveolar regeneration after viral infection” the authors wrote.
The discovery of peroxisomes’ role in controlling inflammation and aiding in lung tissue repair suggests that targeting treatment to these organelles could be a valuable strategy for mitigating chronic lung damage across a range of respiratory illnesses.
“Ultimately, we want to develop peroxisome-targeting therapies to give patients the chance to breathe more easily again and get back to their normal lives,” pointed out Sun.
Additional research is needed before these therapies are used in human patients, but the parallels between human and mouse inflammation and macrophage response are promising. Further, 4-PBA is already an FDA-approved drug for humans, currently used to treat increased levels of ammonia in the blood. Utilizing drugs for new purposes may offer relief to those suffering from long COVID and other persistent post-infection respiratory symptoms sooner than typically expected.