In patients with severe and long-lasting COVID-19, blood clotting disorders have often been observed. Now, researchers from Linköping University (LiU), Sweden, have found that the body’s immune system can affect the spike protein on the surface of the SARS-CoV-2 virus, leading to the production of a protein misfolded tip called amyloid. The discovery of a possible link between harmful amyloid production and symptoms of COVID-19 has been published in the Journal of the American Chemical Society.
In those with severe, long-term COVID-19, organs other than the lungs may be severely affected. Complex symptoms and damage to, for example, the heart, kidneys, eyes, nose and brain, as well as disturbed blood clotting, may persist. Why disease affects the body in this way is largely a mystery. Now, LiU researchers have discovered a biological mechanism that has never been described before, and which may 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 symptoms related to COVID-19 and those seen in diseases caused by misfolded proteins.
The functions of proteins are strongly affected by the fact that proteins are folded in specific ways that give rise to a specific three-dimensional structure. In addition to this form, a protein can also take an alternative form. Over 30 different proteins are known to have this type of alternate shape, which is associated with disease. This alternative folded protein is called amyloid. LiU researchers wondered if the virus that causes COVID-19, SARS-CoV-2, contains a protein that can create amyloid. They were particularly interested in the spike protein on the surface of the virus, which the virus uses to interact with and infect cells in the body.
Using a computer simulation, the researchers found 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. They produced, among other things, so-called fibrils, which look like long threads when examined under an electron microscope.
But do these fibrils appear spontaneously? It is well known that many diseases, such as Alzheimer’s disease, are preceded by a process in which the body cuts large proteins into smaller pieces, which in turn can produce the harmful amyloid. In their study, the researchers show that an enzyme in white blood cells of the immune system can cut through the spike protein of the coronavirus. When the spike protein is cut, it produces the exact piece of protein that the researchers analyze is most likely to produce amyloid. This enzyme is released in large quantities by a type of white blood cells, neutrophils, which are released early during infections such as COVID-19. When researchers mixed a pure spike protein with this enzyme, called neutrophil elastase, unusual fibrils were produced.
“We have never seen fibrils as perfect, yet frightening, as those of the amyloid-producing SARS-CoV-2 spike protein and its bits. Fibrils from the full-sized spike protein branched like limbs on a body. Amyloids don’t usually branch like that. We believe this is due to the characteristics of the spike protein,” says Per Hammarström, a professor in the Department of Physics, Chemistry and Biology (IFM) at the Linkoping University.
Previous research, including a study by South African researchers, indicated that the spike protein may be involved in the production of small blood clots. Blood contains the protein fibrin, which helps blood clot when a vessel is damaged so that the hole closes and stops bleeding. When the wound has started to heal, the coagulate is thought to be broken up by plasmin, which is also found in the blood. The LiU researchers mixed bits of amyloid-producing protein from the spike protein with these body substances in test tubes and found that the fibrin coagulate that was then produced could not be broken down from the usual way by plasmin. This newly discovered mechanism may be behind the production of similar micro blood clots that have been seen in severe, long-term COVID-19. Disrupted blood clotting is also seen in many amyloid-related diseases.
“We can see that the spike protein, when affected by our own immune system, can produce amyloid structures, and this can potentially affect our blood clotting. We believe this finding is important for many areas of research. , and we hope that other researchers will consider the questions it raises,” says Sofie Nyström, associate professor at IFM and another author of the study.
The research was funded by the Swedish Research Council.
Nyström, S & Hammarström, P., (2022) SARS-CoV-2 spike protein amyloidogenesis. Journal of the American Chemical Society. doi.org/10.1021/jacs.2c03925.