A RUB research team has found out which mechanisms the coronavirus uses to attack the heart – and how it can be stopped.
The Sars-Cov-2 coronavirus can cause severe organ damage in humans. Heart complications are also one of the consequences of a Covid 19 infection. The severe acute respiratory syndrome triggered by corona is usually associated with additional stress on the heart, especially in people with weak hearts or other pre-existing cardiac diseases. The virus also attacks the heart directly, causing myocarditis and heart failure. But how does the virus get into the heart? And how can it be stopped?
Doctor Dr. Nazha Hamdani, who heads the research area for molecular and experimental cardiology at the University Hospital Bochum. The researcher closely followed the virus’ journey into the heart and discovered a new mechanism of entry and damage: the virus docks onto the heart cells using so-called extracellular vesicles and exosomes, i.e. particles outside the cell, and infects them.
Our study shows for the first time that there is another mechanism that the virus uses to get through the bloodstream into the human heart.- Nazha Hamdani
In order to track down the new entry mechanism, the research team at the University Hospital analyzed the blood sera and heart tissue structures of patients suffering from Covid-19 and those who died from the disease using histochemical methods and microscopy.
Virus detected in heart cells
In a first step, Hamdani’s team provided evidence that the virus can actually and directly be detected in the cells of the heart muscle. “Our observations show that the virus exerts pressure on the heart muscle, attacks and weakens the force of contraction, ie the pumping function of the heart,” says Hamdani.
But how does the virus penetrate the heart in the first place? In previous studies on Sars-Cov-2, it was already possible to demonstrate that the novel virus attaches itself to a certain surface molecule of the human cell, the angiotensin-converting protein, via an enzyme, the so-called spike protein, which sits on the outside of the virus envelope. Enzyme 2 (ACE-2), binds. “The virus penetrates the cell interior via the ACE-2 receptor and then multiplies. This process has already been observed in the lungs, intestines, kidneys and liver ”, Hamdani summarizes the results of international research groups so far. Since ACE-2 can also be found on the cell surface of the heart, the Bochum doctor assumed that the virus would also attack the heart in this way.
To their astonishment, Hamdani and her team found the infected ACE-2 receptor only in the endothelium, the cell layer on the inner surface of the blood cells, and in extracellular particles, but not in the heart muscle cells. For the doctor it was clear: “The virus infection of human cells succeeds via ACE-2, but the virus seeks its way into the heart independently of it”. So there had to be other factors that enable the virus to enter the heart’s vascular cells. Hamdani and her team found what they were looking for in just four months.
Discovered a new mechanism
The key are what are known as extracellular vesicles. These lie outside the cells and are responsible for cell-to-cell communication. They are able to transport molecules, and thus also the messenger RNA of the virus, from infected cells to healthy cells. “Like a taxi that drives through the bloodstream and distributes the genetic information of the virus,” explains Hamdani.
The research team made the vesicles visible using a fluorescent dye, so-called double gold marking, and then observed them through a special light microscope, a confocal microscope, and an electron microscope. They were able to clearly identify the vesicles including the virus and components such as double-stranded RNA and spike protein in the blood and heart cells of severely infected patients. Follow-up experiments should show whether other organ cells are also attacked via this additional mechanism.
Alternative entry gate
In addition, the Bochum researchers were able to support the existing findings that the virus also uses the protein Neuropilin-1 (NRP-1) as a gateway into the cells. “Neuropilin lies on the outer wall of the epithelium, the top layer of cells in human skin, and thus makes it easier for the virus to penetrate. We measured an increased NPR-1 activity in the heart cells. This indicates that neuropilin-1 is an alternative receptor for Sars-Cov-2 entry alongside the ACE-2 receptor, ”Hamdani explains the important find. Neuropilin produces the messenger substance interleukin-6, which in turn regulates the inflammatory reaction of the organism and is essential for immune defense processes. If the production of interleukin-6 increases, this can lead to cell damage and cell death.
Why the novel Sars-Cov-2 is so virulent?
Hamdani’s research shows that this means that several mechanisms are available for the coronavirus to spread in human organs. “The fact that the new virus is able to distribute itself independently of receptors via infected endothelial vesicles sets it apart from its predecessor Sars-Cov-1 and makes it a lot more virulent,” explains Hamdani. “The susceptibility to infection is also favored by an inflamed and oxidized cell environment, as often occurs in the elderly, people with high blood pressure, diabetics or those affected by obesity,” the doctor continues. Hamdani has been researching the pathophysiological causes of heart disease for years. What they all have in common: inflamed and oxidized vascular cells. Such a cell environment also increases the risk of Covid 19 patients
Breakthrough in Covid-19 therapy
Since the beginning of the corona pandemic, therapies have been sought that can contain the virus infection and prevent severe disease. The new mechanism that the Bochum research team has uncovered holds a promising therapeutic approach in store. It could be possible to load the extracellular vesicles with a medicinal cocktail of antibodies, anti-oxidants and anti-inflammatory agents that stop the virus from spreading, reduce inflammation levels and boost the immune system. “Our future cocktail drug would help people who have not yet been vaccinated but are already infected,” says Hamdani, explaining the therapeutic potential. It would also work against all virus variants. “The drug should prevent entry into the heart and other organs, regardless of the type of mutant,” says the researcher.
Featured image: A RUB doctor has discovered how the coronavirus penetrates the heart muscle cells. © Roberto Schirdewahn
Provided by Ruhr Universitat Bochum