Coronavirus spike protein activated natural immune response, damaged heart muscle cells

Research Highlights:

  • Researchers have demonstrated for the first time a potential pathway for the heart-damaging SARS-CoV-2 spike protein.

  • In a study evaluating mice and human heart cells, the SARS-CoV-2 spike protein inflamed heart muscle cells, which can lead to heart damage.

Embargoed until 8 a.m. CT/9 a.m. ET, Monday, July 25, 2022

(NewMediaWire) – July 25, 2022 – CHICAGO Heart damage is common in patients hospitalized with COVID-19, leading many to wonder how the virus affects the heart. Now, researchers have found that the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus can lead to heart muscle damage through the inflammatory process, according to preliminary research that will be presented at the cardiovascular course. basis of the American Heart Association. Sciences Scientific Sessions 2022. The meeting, held in Chicago July 25-28, features the latest research in basic and translational cardiovascular science.

The spike protein is on the surface of SARS-CoV-2, the virus that causes COVID-19. The spike proteins lock onto receptors known as angiotensin converting enzyme 2 (ACE2) on target cells. The spike protein facilitates entry of the virus into healthy cells, which is the first step in infection. In addition to infecting the lungs, the virus can also spread to other organs, leading to further bodily harm, severe infection and, in some people, death.

“It is already known from the clinical side that COVID-19 infection can induce heart damage, however, what we don’t know are the mechanistic details of how this occurs. What we suspect is that the spike protein has unknown pathological roles,” said Zhiqiang Lin, Ph.D., lead study author and assistant professor at the Masonic Medical Research Institute in Utica, New York. “Our data shows that the spike protein of SARS-CoV-2 damages heart muscle. That’s why it’s important to get vaccinated and prevent this disease.”

“The host’s natural immunity is the first line of defense against invading pathogens, and heart muscle cells have their own natural immune machinery. Activation of the body’s immune response is essential to fight viral infection; however, it can also impair heart muscle cell function and even lead to cell death and heart failure,” Lin said.

The researchers studied whether the SARS-CoV-2 spike protein activated the natural immune response in heart muscle cells. HCoV-NL63 is a coronavirus that infects the respiratory system without causing heart damage, although its spike protein also uses ACE2 to mediate virus entry. They investigated the potential ability to cause heart disease of the SARS-CoV-2 spike protein and the NL63 spike protein. Their results showed that the SARS-CoV-2 spike protein activated the natural immune response in cardiac muscle cells and damaged the heart, but the NL63 spike protein did not.

“The fact that SARS-CoV-2’s spike protein activates the natural immune response may explain the high virulence compared to other coronaviruses,” Lin said. “TLR4 signaling is the primary pathway that activates the body’s natural immune response, and the SARS-CoV-2 spike protein activates TLR4, not the usual flu spike protein.”

To study the impact of the SARS-CoV-2 spike protein on the heart, the researchers cloned the SARS-CoV-2 spike protein and the NL63 spike protein into the viral vector AAV9. The AAV9 viral vector was administered to laboratory mice to activate the spike protein in heart muscle cells. They found that the AAV9-mediated SARS-CoV-2 spike protein, not the NL63 spike protein, caused cardiac dysfunction, hypertrophic remodeling (enlargement), and cardiac inflammation.

In lab tests on heart cells grown in dishes, researchers also observed that the SARS-CoV-2 spike protein made heart muscle cells significantly larger than cells without either advanced proteins. “We found direct evidence that the SARS-CoV-2 spike protein is toxic to heart muscle cells,” Lin said.

During this study, the researchers also examined a heart biopsy from a deceased patient with inflammation due to COVID-19. They detected the SARS-CoV-2 spike protein and the TLR4 protein in heart muscle cells and other cell types. In contrast, these two proteins were absent in a biopsy of a healthy human heart. “This means that once the heart is infected with SARS-CoV-2, it will activate TLR4 signaling,” Lin said. “In addition to directly damaging heart muscle cells, the spike protein itself is highly inflammatory and can cause systemic inflammation that indirectly causes heart problems.”

ACE2 is an important enzyme controlling blood pressure. SARS-CoV-2 infection can impair ACE2 function, which in turn leads to increased blood pressure and, therefore, injures the heart. SARS-CoV-2 can also damage the heart in other unknown ways.

“Our study provides two lines of evidence that the SARS-CoV-2 spike protein does not need ACE2 to injure the heart. First, we found that the SARS-CoV-2 spike protein injured the hearts of lab mice. Different from ACE2 in humans, ACE2 in mice does not interact with SARS-CoV-2 spike protein, therefore, SARS-CoV-2 spike protein did not hurt the heart by directly disrupting the function of ACE2. Second, although the SARS-CoV-2 and NL63 coronaviruses use ACE2 as a receptor to infect cells, only the SARS-CoV-2 spike protein interacted with TLR4 and a inflamed heart muscle cells. Therefore, our study presents a novel pathological role independent of the SARS-CoV-2 spike protein ACE2,” Lin said.

This research is the first step in determining whether the SARS-CoV-2 spike protein affects the heart. The researchers now plan to study how SARS-CoV-2 spike proteins cause inflammation in the heart. There are two potential ways: the first is that the spike protein is expressed in virus-infected heart muscle cells and thus directly activates inflammation; the second is that the virus spike protein is released into the bloodstream, and circulating SARS-CoV-2 spike proteins damage the heart.

Co-authors are Caroline Sheldon, BA; Steven Negron, BA; Chase W. Kessinger, Ph.D.; Bing Xu, Ph.D.; William T. Pu, MD; and Chieh-Yu Lin, MD, Ph.D. Author disclosures are listed in the abstract. No funding has been reported for this study.

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Additional Resources:

The American Heart Association Cardiovascular Science Core Grand Rounds (BCVS) is the premier global meeting dedicated to the latest advances in basic and translational cardiovascular sciences. The virtual meeting is being held at the Chicago Hilton, July 25-28, 2022. The main purpose of the meeting is to bring together scientists from around the world with the common goal of uncovering pathways to cardiovascular therapeutics and promoting cardiovascular health. Sessions will focus on new therapies and insights into cardiovascular disease, as well as research in areas such as microRNAs, cardiac cell and gene therapy, cardiac development, as well as tissue engineering and iPS cells. . The Board of Basic Cardiovascular Sciences of the American Heart Association has planned the 2022 BCVS Scientific Sessions program which will be of particular interest to basic cardiovascular scientists, molecular/cellular biologists, physiologists, translational researchers, clinical trials, practicing cardiologists, cardiovascular nurses and pharmacists. Follow the conference on Twitter at #BCVS22.

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