Researchers at the Center for Precision Disease Modeling at the University of Maryland School of Medicine (UMSOM) determined how a specific protein in the SARS-CoV-2 virus that causes COVID-19 damages heart tissue. They then used a drug to reverse the toxic effects of the protein on the heart.
Their finding was based on studies of Drosophila and mouse heart cells, and was published in Communications Biology.
Compared to virus-uninfected people, people infected with COVID-19 have a significantly higher risk of developing myocardial inflammation, abnormal heart rhythm, blood clots, stroke, heart attack, and heart failure at least one year after infection. Although scientists have rapidly developed vaccines and drugs to reduce the severity of COVID-19 disease, these therapies do not protect the heart or other organs from damage that may be caused by even minor infections.
“To treat patients for a long time, we must first understand the mechanisms that lead to disease. Our study suggests that individual SARS-CoV-2 proteins can cause significant damage to specific tissues of the body, similar to findings for other viruses such as HIV and Zika virus,” said Dr. Zhe Han, senior author, professor of medicine, and director of the Center for Precision Disease Modeling at the University of Michigan Medical School. “By identifying these damage processes in each tissue, we can test drugs to see if any drugs can reverse this damage; those drugs that show promise can be further tested in clinical research studies.”
Last year, Dr. Han and his team discovered the most toxic SARS-CoV-2 protein in studies using Drosophila and human cells. They found that selinexor, a promising drug, reduced the toxicity of one of these proteins, but not of another protein called Nsp6.
In their latest study, they found that Nsp6 was the most toxic SARS-CoV-2 protein in the Drosophila heart. Next, they found that the Nsp6 protein hijacks cells in the Drosophila heart, initiates the glycolytic process, and allows cells to burn glucose for energy. Typically, heart cells use fatty acids as an energy source, but in heart failure, these cells switch to glucose metabolism in an attempt to repair damaged tissue. The researchers also found that the Nsp6 protein destroys mitochondria, the power source of cells, which generate energy through glucose metabolism, thereby increasing damage.
The team then used 2-deoxyglucose (2DG) to block glucose metabolism in Drosophila and mouse heart cells. They found that the drug reduced heart and mitochondrial damage caused by the Nsp6 viral protein.
“We know that some viruses hijack the cellular mechanisms of infected animals, change their metabolism, and steal the energy source of cells, so we suspect that SARS-CoV-2 does something similar. Viruses can also use by-products of sugar metabolism as cornerstones for making more viruses,” Dr. Han said. “Therefore, we predict that this drug that alters cardiac metabolism to preinfection is harmful to the virus because it cuts off both the energy supply to the virus and eliminates segments required for viral replication.”
Fortunately, 2DG is cheap and often used in laboratory research, the researchers said. Although 2DG has not been approved by the US Food and Drug Administration for the treatment of disease, the drug is currently undergoing clinical trials for the treatment of COVID-19 in India.
Many Americans who recover from COVID develop dangerous heart disease weeks or months later, and we need to understand the underlying causes of this. As this study elucidates the pathway of the Nsp6 protein, we can improve our therapeutic goals for future studies with the ultimate goal of reversing further cardiac damage in these patients.
