In severe covid-19 and long-term covid, disorders of blood coagulation often occur. Now, researchers at LiU have discovered that the body’s immune system can affect the nail protein on the surface of the sars-cov-2 virus so that it forms misfolded protein, so-called amyloid. The findings point to a possible link between harmful amyloid formation and covid-19 symptoms.

Electron microscopy image of amyloid formed by nail protein from coronavirus.

Electron microscopy image of amyloid from the nail protein of the sars-cov-2 virus. When nail protein is mixed with the enzyme neutrophil elastase in test tubes, branched protein fibrils are formed which may cause coagulation disorders in covid-19.EMSIS

In severe covid-19 disease and long-term covid, more organs than the lungs can be seriously affected. Complex disease symptoms and damage to, for example, the heart, kidneys, eyes, nose, brain and disorders of blood coagulation can persist for a long time. Why the disease affects the body in this way is largely another mystery. Now, researchers at Linköping University have found a biological mechanism that has never been described before and that may prove to be part of the explanation.

The research team is studying diseases caused by misfolded proteins, of which Alzheimer’s disease in the brain is the best known. The researchers noted that there are many similarities between covid-related symptoms and those seen in diseases where misfolded proteins pose problems.

The function of proteins is very strongly linked to the fact that the protein is folded in a certain way which gives it a specific 3-dimensional structure. In addition to this form, a protein may take an alternative form. Over 30 different proteins are known to have such an alternately folded form that is associated with disease. This alternative folding of the protein is called amyloid. LiU researchers wondered if the virus that causes covid-19, sars-cov-2, has a protein that can form amyloid. They were particularly interested in the nail protein on the surface of the virus, which the virus uses to interact with the body’s cells and infect them.

The researchers found via computer simulation that the coronavirus’ nail protein contains seven different sequences that could potentially form amyloid. Three of the seven sequences met the researchers’ criteria for being counted as amyloid-forming. Among other things, they formed so-called fibrils, which look like long strands when examined under an electron microscope.

But do these fibrils arise by themselves? It is known that many amyloid diseases, such as Alzheimer’s disease, are preceded by a process in which the body cuts large proteins into smaller pieces of protein that can form harmful amyloid. In the study, published in the  Journal of the American Chemical Society , the researchers show that an enzyme from the white blood cells of the immune system can cut up the nail protein of the coronavirus. When the nail protein is cut, the very piece of protein that according to the researchers’ analyzes is most likely to form amyloid is formed. This enzyme is released in large quantities from a type of white blood cell, neutrophils, which is released at an early stage in infections such as covid-19. When the researchers mixed pure nail protein with the enzyme called neutrophil elastase, unusual fibrils formed.

– We have never seen such fine, but scary, fibrils as from the amyloid-forming sequence in the nail protein in sars-cov-2. The fibrils from the nail protein grew out as branched arms from a body and amyloids are not normally branched in that way. We believe that it has to do with properties of the nail protein, says Per Hammarström, professor at the Department of Physics, Chemistry and Biology, IFM.

Previous research, including a study by South African researchers, has indicated that the nail protein may be involved in the formation of small blood clots. There is the protein fibrin in the blood, which causes the blood to coagulate when a vessel is damaged, so that the hole is closed and it stops bleeding. When the injury has begun to heal, the clot should be dissolved by the plasmin, which is also found in the blood. The Linköping researchers mixed amyloid-forming protein pieces from the nail protein with these body-specific substances in test tubes, and saw that the fibrin clots that then form cannot be dissolved in the normal way by plasmin. This newly discovered mechanism could be behind the formation of similar microbial clots that have been observed in both severe covid-19 and long-term covid. Disorders of blood coagulation are also seen in many amyloid diseases.

– We see that the nail protein under the influence of our own immune system can form amyloid structures, and that it can potentially affect our blood coagulation. We believe that these findings can be important in many different research fields and we hope that other researchers will look further at various issues that are raised, says Sofie Nyström, senior lecturer at IFM, the other researcher behind the study.

The study has been funded with the support of the Swedish Research Council.

Article: Amyloidogenesis of SARS-CoV-2 Spike Protein , Sofie Nyström and Per Hammarström, (2022), Journal of the American Chemical Society , published online May 17, 2022, doi: 10.1021 / jacs.2c03925

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