Impaired blood clotting has been observed frequently in patients with severe and long-lasting COVID-19. Now, researchers at Linköping University (LiU), Sweden, have discovered that the body’s immune system can affect the spike protein on the surface of the SARS-CoV-2 virus, resulting in the production of a misfolded spike protein called amyloid. The discovery of a possible link between harmful amyloid production and symptoms of COVID-19 was published in Journal of the American Chemical Society.
In patients with severe and long-term COVID-19, organs other than the lungs can be severely affected. Complex symptoms and damage to the heart, kidneys, eyes, nose and brain, for example, as well as blood clotting disorders can persist. Why the disease affects the body in this way is largely a mystery. Now, researchers at LiU have found a biological mechanism never before described that could be part of the explanation.
The research team studies diseases caused by misfolded proteins, of which Alzheimer’s disease in the brain is the best-known example. The researchers noted that there are many similarities between COVID-19-related symptoms and those seen in diseases caused by misfolded proteins.
The functions of proteins are greatly affected by the fact that proteins are folded in a specific way, resulting in a specific three-dimensional structure. In addition to this form, a protein can also take on an alternative form. Over 30 different proteins are known to have this type of alternative shape, which is associated with disease. This alternative folded protein is called amyloid. The LiU researchers wondered if the virus that causes COVID-19, SARS-CoV-2, contains a protein that can form amyloid. They were particularly interested in the spike protein on the surface of the virus, through which the virus interacts with and infects the body’s cells.
Using computer simulations, the researchers discovered that the coronavirus spike protein contained seven different sequences that could potentially produce amyloid. Three of the seven sequences met the researchers’ criteria to be counted as amyloid-producing sequences when tested experimentally. Among other things, they produced what are known as fibrils, which look like long threads under the electron microscope.
But do these fibrils form spontaneously? It is well known that many diseases, such as Alzheimer’s, are preceded by a process in which the body breaks down large proteins into smaller pieces, which in turn can create the harmful amyloid. In their study, the researchers show that an enzyme from the white blood cells of the immune system can cut up the spike protein of the coronavirus. If you crush the spike protein, you get exactly the piece of protein that, according to the researchers’ analysis, is most likely to produce amyloid. This enzyme is released in large quantities by a type of white blood cell called neutrophils, which are released early in infections like COVID-19. When the researchers mixed pure spike protein with this enzyme called neutrophil elastase, unusual fibrils were produced.
“We have never seen fibrils as perfect but frightening as these made from the amyloid-producing SARS-CoV-2 spike protein and parts of it. The fibrils that emanate from the full-size spike protein branch out like limbs on a body. Amyloids don’t usually branch that way. We believe that this is due to the properties of the spike protein,” says Per Hammarström, professor at the Institute of Physics, Chemistry and Biology (IFM) at Linköping University.
Previous research, including a study by South African researchers, has shown that the spike protein may be involved in the formation of small blood clots. The blood contains the protein fibrin, which helps the blood clot when a blood vessel is injured, closing the hole and stopping the bleeding. Once the wound has started to heal, the aim is to use plasmin, which is also found in the blood, to break up the clot. The LiU researchers mixed amyloid-producing protein pieces from the spike protein with these body substances in test tubes and found that the resulting fibrin coagulum could not be broken down by plasmin in the usual way. This newly discovered mechanism could be behind the production of similar micro blood clots seen in both severe and long-term COVID-19. Impaired blood coagulation is also observed in many amyloid-related diseases.
“We can see that when the spike protein is influenced by our own immune system, it can produce amyloid structures and that this can potentially affect our blood clotting. We believe this discovery has implications for many areas of research, and we hope other researchers will explore the questions it raises,” says Sofie Nystrom, associate professor at IFM and the other author of the study.
The research was funded by the Swedish Research Council.
Nystrom, S. & Hammarstrom, P., (2022) Amyloidogenesis of SARS-CoV-2 Spike Protein. Journal of the American Chemical Society. doi.org/10.1021/jacs.2c03925.