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UVA School of Medicine scientists have discovered how severe COVID-19 can destroy immune cells’ ability to repair the lungs, helping explain the lingering effects of long COVID. The findings suggest a new treatment approach for long COVID as well as other conditions, both short-term and chronic, caused by respiratory infections such as the flu.

Led by UVA’s Jie Sun, PhD, the researchers found that severe viral infections including COVID-19 and the flu can gravely damage a key organelle inside immune cells called macrophages. Macrophages direct lung repair after tissue damage, but their ability to do so is crippled by the loss of the critical organelles, called peroxisomes, Sun and his team found.

Promisingly, the UVA scientists found that they could enhance the damaged organelles’ ability to function — and improve the immune system’s ability to heal lung damage — using a drug that has already been approved by the federal Food and Drug Administration.

“COVID-19 can leave the lungs unable to heal properly by damaging these tiny structures inside our cells. 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 by targeting a tiny organelle inside critical immune cells,” says Sun, of UVA’s Carter Center for Immunology Research and UVA’s Division of Infectious Diseases and International Health. “A tiny organelle can have big roles! I hope our work could lead to new peroxisome-centric therapies that can help people suffering from long COVID.”

Understanding Long COVID

Peroxisomes are often overlooked and under studied, the researchers note. The organelles are tiny structures known to play vital roles in breaking down toxins and fats within cells. But UVA’s new research suggests that they are also critical to resolving inflammation after severe viral lung infections. As such, they could represent an important avenue for treating acute and chronic conditions that follow those infections.

Sun and his collaborators found that severe COVID infections “drastically” alter peroxisomes inside macrophages, they report in a new scientific paper. This dramatic “remodeling” inhibited peroxisome development and caused them to degrade, robbing them of their ability to function properly. The result was stubborn inflammation and lung scarring. The scientists found persistent peroxisome impairment in both lab mice and human patients after severe COVID-19 infections.

They were able to reverse that impairment in early testing, however, using sodium phenylbutyrate, a drug already approved by the FDA to treat patients with high levels of ammonia in their blood. More research is needed before the drug could be deployed for treating long COVID, but the scientists say their findings warrant additional study. 

Further, the discovery of the peroxisomes’ role in controlling inflammation and in repairing alveola (air sacs) in the lungs suggests that targeting them could be useful for treating stubborn post-infection problems caused by influenza and other respiratory viruses, Sun says. 

“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],” he says. “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.”

Findings Published

The researchers have published their findings in the journal Science. The research team consisted of Xiaoqin Wei, Wei Qian, Harish Narasimhan, Ting Chan, Xue Liu, Mohd Arish, Samuel Young, Chaofan Li, In Su Cheon, Jane Qing Yu, Gislane de Almeida Santos, Xiao-Yu Zhao, Eric V. Yeatts, Olivia J. Spear, Megan Yi, Tanyalak Parimon, Yinshan Fang, Young S Hahn, Timothy N.J. Bullock, Lindsay A. Somerville, Mark H. Kaplan, Anne I. Sperling, Yun Michael Shim, Robert Vassallo, Peter Chen, Sarah E. Ewald, Anja C. Roden, Jianwen Que, Dianhua Jiang and Sun. 

The research was supported by the National Institutes of Health, grants AI147394, AG069264, AI112844, HL170961, AI176171, AI154598, R01HL132287, R01HL167202, R01HL132177, F31HL170746, T32AI007496, R01HL155759, R01HL159953, R01HL172990, P01-HL108793, HL159675, HL152293, AI163753 and R01DK122737.

UVA has filed a patent application on the concept of targeting peroxisomes for treating acute and chronic conditions after viral injuries.

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