Baltimore, MD – Researchers at the University of Maryland School of Medicine’s (UMSOM) Center for Precision Disease Modeling have pinpointed a specific protein within the SARS-CoV-2 virus that inflicts damage on heart tissue, and have identified a drug that shows promise in reversing these detrimental effects. This breakthrough, detailed in the September 30, 2022, issue of the prestigious journal Communications Biology, a publication under the Nature umbrella, sheds critical light on the mechanisms behind cardiovascular complications observed in COVID-19 patients and offers a potential therapeutic avenue.
The ramifications of COVID-19 infection extend far beyond the initial respiratory illness, with individuals facing a significantly elevated risk of developing a spectrum of serious cardiac issues for at least a year post-infection. These complications include inflammation of the heart muscle (myocarditis), irregular heart rhythms (arrhythmias), the formation of blood clots, stroke, heart attacks, and ultimately, heart failure. While the rapid development of vaccines and antiviral medications has been instrumental in mitigating the severity of acute COVID-19 illness, these interventions have not proven to be a comprehensive shield against the insidious cardiac damage that can occur even from mild infections.
Unraveling the Molecular Assault on the Heart
"To effectively treat patients in the long run, we must first gain a profound understanding of the underlying mechanisms driving the disease," stated senior author Zhe Han, PhD, Professor of Medicine and Director of the Center for Precision Disease Modeling at UMSOM. "Our research demonstrates that individual SARS-CoV-2 proteins possess the capacity to inflict substantial damage on specific tissues within the body, a phenomenon observed with other viral pathogens like HIV and Zika. By meticulously identifying these injury pathways in each affected tissue, we can then systematically evaluate potential drugs to determine if any can reverse this damage. Promising candidates can subsequently be advanced to clinical research studies for further validation."
This latest study builds upon prior work by Dr. Han and his team. In a significant finding last year, they identified the most toxic proteins produced by SARS-CoV-2 through studies employing fruit flies and human cells. During that investigation, they identified the drug selinexor as a potential candidate capable of reducing the toxicity of one of these key viral proteins. However, it did not show efficacy against another particularly harmful protein, known as Nsp6.
Nsp6: The Virulent Culprit
In their most recent research, the UMSOM team focused their attention on Nsp6, and their findings underscore its particularly virulent nature in the context of cardiac health. They discovered that Nsp6 emerged as the most toxic SARS-CoV-2 protein within the fruit fly heart.
Further investigation revealed a disturbing modus operandi: the Nsp6 protein actively hijacks the machinery of the fruit fly’s heart cells. Its primary target is the induction of glycolysis, a metabolic pathway that enables cells to break down glucose, a simple sugar, for energy. This is a crucial deviation from the heart’s typical energy production strategy. Normally, healthy heart cells primarily rely on fatty acids for their energy needs. They only shift towards sugar metabolism, including glycolysis, as a compensatory mechanism when the heart is under stress or experiencing failure, attempting to generate sufficient energy to repair damaged tissue.
The researchers discovered that Nsp6 not only forces this metabolic shift but also inflicts additional damage by disrupting the mitochondria – the powerhouses of the cell. Mitochondria are responsible for generating the vast majority of cellular energy through oxidative phosphorylation, a process that depends on the efficient metabolism of sugars and fats. By impairing mitochondrial function, Nsp6 cripples the cell’s ability to produce energy, exacerbating the damage already initiated by the forced metabolic switch.
A Metabolic Intervention: The Promise of 2DG
Recognizing the critical role of metabolic dysregulation, the research team then explored a targeted intervention. They utilized the drug 2-deoxy-D-glucose (2DG) to block the aberrant sugar metabolism pathway in both fruit flies and mouse heart cells. The results were encouraging: 2DG effectively mitigated the cardiac and mitochondrial damage attributed to the Nsp6 viral protein.
"We understand that certain viruses have evolved the ability to hijack the host animal’s cellular machinery, altering its metabolism to essentially steal the cell’s energy sources," explained Dr. Han. "We hypothesized that SARS-CoV-2 operates in a similar fashion. Furthermore, viruses can leverage the byproducts of sugar metabolism as essential building blocks for their own replication. Therefore, we predict that a drug like 2DG, which effectively resets the heart’s metabolism back to its pre-infection state, would be detrimental to the virus. It would simultaneously cut off its energy supply and eliminate the necessary components for its replication."
Broader Implications and Future Directions
The implications of these findings are significant, particularly given the prevalence of cardiovascular sequelae following COVID-19. The drug 2DG is notably inexpensive and is a commonly used compound in laboratory research settings. While it has not yet received approval from the U.S. Food and Drug Administration (FDA) for therapeutic use in disease treatment, it is currently undergoing clinical trials for COVID-19 treatment in India, underscoring its potential as a repurposed drug.
Mark T. Gladwin, MD, Vice President for Medical Affairs at the University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean of UMSOM, emphasized the urgency and importance of this line of inquiry. "Regrettably, a substantial number of Americans who have recovered from COVID-19 are subsequently developing serious cardiac conditions weeks or months later. It is imperative that we uncover the fundamental reasons behind this phenomenon," Dr. Gladwin stated. "This research, by elucidating the specific pathways affected by the Nsp6 protein, provides us with a refined target for future therapeutic development. Our ultimate goal is to develop treatments capable of reversing further heart damage in these vulnerable patients."
The economic burden of long-term COVID-19 complications, often referred to as "long COVID," is substantial, encompassing not only direct medical costs but also lost productivity and diminished quality of life. Cardiovascular issues represent a significant component of this burden, necessitating innovative solutions. The identification of specific viral proteins responsible for organ damage, as demonstrated by this study, opens the door for more precise and targeted therapeutic strategies, potentially reducing the need for broad-spectrum interventions with their associated side effects.
A Chronology of Discovery
- Prior Year: Researchers at UMSOM’s Center for Precision Disease Modeling identify the most toxic SARS-CoV-2 proteins through studies with fruit flies and human cells. They discover the drug selinexor shows promise in reducing the toxicity of one protein but not Nsp6.
- Current Study (Published Sept. 30, 2022):
- Researchers identify Nsp6 as the most toxic SARS-CoV-2 protein in the fruit fly heart.
- They discover Nsp6 hijacks heart cells to induce glycolysis, the breakdown of sugar for energy.
- They find Nsp6 disrupts mitochondrial function, further impairing energy production.
- The drug 2-deoxy-D-glucose (2DG) is used to block sugar metabolism in fruit flies and mouse heart cells.
- 2DG is found to reduce heart and mitochondrial damage caused by Nsp6.
- Future Outlook: The research team aims to further investigate 2DG and potentially other drugs for their ability to reverse Nsp6-induced cardiac damage, with the eventual goal of clinical trials in humans.
Supporting Data and Context
The prevalence of cardiovascular complications following COVID-19 has been a subject of numerous studies. For instance, a large retrospective study published in the journal Circulation in March 2022 analyzed data from over 150,000 individuals and found that individuals who had contracted COVID-19 had a significantly increased risk of a wide range of cardiovascular conditions in the year following their infection, including stroke, transient ischemic attack, heart failure, myocarditis, and arrhythmias, compared to a matched control group. This heightened risk was observed across different age groups and in individuals with and without pre-existing cardiovascular risk factors, underscoring the systemic impact of the virus.
The economic impact of long COVID, including cardiovascular sequelae, is also a growing concern. A report by the U.S. Congressional Budget Office in 2022 estimated that long COVID could reduce the supply of labor by hundreds of thousands of full-time equivalent workers, with significant implications for economic growth. Cardiovascular issues, in particular, can lead to chronic disability, prolonged recovery periods, and reduced earning potential, thus amplifying the overall economic burden.
The research was supported by the University of Maryland, Baltimore Institute for Clinical and Translational Research COVID-19 Accelerated Translational Incubator Pilot (ATIP) grant, a testament to the collaborative and targeted efforts to address the ongoing public health crisis. This funding mechanism highlights the institution’s commitment to rapidly translating promising laboratory findings into potential clinical applications.
Official Responses and Broader Impact
The findings from the UMSOM team have been met with considerable interest within the scientific and medical communities. The clear identification of a specific viral protein, Nsp6, as a direct contributor to cardiac damage provides a concrete target for future research and drug development. This is a significant step forward from earlier, more generalized understandings of how SARS-CoV-2 affects the cardiovascular system.
The broader implications of this research extend beyond COVID-19. The principles of identifying specific viral proteins responsible for tissue damage and then testing drugs to reverse those effects can be applied to other viral diseases that have significant long-term health consequences. This approach aligns with the growing field of precision medicine, which aims to tailor medical treatment to the individual characteristics of each patient and their disease.
By understanding the precise molecular mechanisms of viral injury, researchers can move away from broad, potentially less effective treatments towards highly targeted therapies that address the root cause of the damage. This could lead to more effective interventions, reduced side effects, and ultimately, improved patient outcomes. The identification of 2DG as a potential therapeutic agent for Nsp6-induced cardiac damage is particularly promising due to its existing availability and low cost, which could facilitate its rapid translation into clinical practice if further studies confirm its efficacy and safety.
The ongoing research at the University of Maryland School of Medicine represents a critical advancement in our fight against the long-term consequences of COVID-19. By dissecting the intricate ways in which the virus impacts vital organs like the heart, scientists are paving the way for novel therapies that could significantly alleviate the burden of long COVID and improve the lives of millions worldwide.