In flies and mice, a viral protein increases the rate of energy use by heart cells. But it’s not yet clear if the finding applies to humans.
Since the start of the pandemic, scientists have documented a “spectrum” of potential heart effects of SARS-CoV-2. Now, a team at the University of Maryland School of Medicine has found a specific virus protein can damage the heart—at least in flies and mice.
When a virus enters a host cell, it induces that cell to create specific viral proteins. The SARS-CoV-2 virus contains the genetic information for 29 different proteins, and in a paper published in Communications Biology in September, researchers determined that one of those proteins, Nsp6, supercharges energy usage in heart cells in a way that may cause heart damage.
The researchers first selected 12 of SARS-CoV-2’s proteins with the highest likelihood of instigating a pathogenic response in host cells, as identified by a computational method that predicted their function based on structure. The team then engineered 12 separate lines of fruit flies to each express one of the proteins in their heart cells, and observed the proteins’ effects on mortality, the morphology of the flies’ hearts, and gene expression in the heart cells.
They found that one protein, Nsp6, had a particularly detrimental effect—flies in the Nsp6 transgenic line had a much higher rate of mortality than control flies and showed “pronounced structural and functional damage” in their hearts, according to the paper. In addition, genes for proteins involved in glycolysis, which breaks down glucose into useable energy, were upregulated in the muscular heart cells, or cardiomyocytes, of the Nsp6 flies. The supercharged glycolysis disrupted the function of mitochondria—where some steps in glycolysis take place—within the cardiomyocytes. Eventually, the mitochondrial disruption led to heart failure in the flies, write the researchers in the study.
Study coauthor Zhe Han, a developmental biologist at the University of Maryland School of Medicine, hypothesizes that the upregulation of glycolysis is a matter of survival for the virus—it forces the cell to provide more fuel for viral replication. Since cardiomyocytes are very similar to other muscle cells, it’s possible that muscle pain and weakness experienced by COVID-19 patients are also related to the upregulation of glycolysis caused by Nsp6, Han says.
The team also found that the Nsp6 protein upregulated glycolysis in lab-grown mouse heart cells. The proteins involved in glycolysis are highly conserved between fruit flies and mammals, says Han, so these results may provide insight into how SARS-CoV-2 damages human hearts as well. The authors also tested a possible treatment, a compound called 2-Deoxy-D-Glucose, or 2DG, which downregulates glycolysis. They found that it lessened the deleterious effects of Nsp6 in both flies and mouse cells.
Paul Cheng, a cardiologist at the Stanford University School of Medicine who was not involved in the research, says that while it is an “interesting hypothesis” that SARS-CoV-2’s Nsp6 causes heart damage, there may also be other reasons for such damage after infection, such as myocarditis, which describes heart inflammation and does not involve the pathway described in the paper. Han acknowledges there may be multiple causes of heart damage. “The immune response may also trigger certain stress” in the organ, he says.
Additionally, Cheng says, it’s not clear the extent to which SARS-CoV-2 can enter cardiomyocytes in the first place. “Cardiomyocytes themselves do not seem to express the key receptor for the SARS-CoV-2 virus at a high level,” says Cheng, referring to a protein known as ACE2. Han concedes that there are “still a lot of unknowns” about the extent to which SARS-CoV-2 can enter cardiomyocytes; while cardiomyocyte expression of ACE2 is indeed low, entry of SARS-CoV-2 into cardiomyocytes has been documented.
Regardless, there will likely be another coronavirus pandemic at some time in the future, says Han. While a virus’s spike proteins mutate frequently, the other proteins remain similar across coronaviruses, he says. The next novel coronavirus to infect humans, then, will likely have a different spike protein, but may maintain other proteins such as Nsp6, meaning that any understanding of how SARS-CoV-2 and its proteins affect health could be helpful in combatting it.
Clarification (November 22): References to the University of Maryland have been changed to the University of Maryland School of Medicine.