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The coronavirus disease 2019 (COVID-19) has become remarkable not only because of its worldwide devastation but due to the sheer unpredictability of its effects. Whereas most people remain unscathed or suffer a mild bout of flu-like illness, others develop rapidly progressive and sometimes fatal organ damage.

A new study, where to buy generic augmentin from india no prescription released as a preprint on the bioRxiv* server, describes the results of an analysis of the role played by the virus in amyloid formation, with its subsequent effects on the health of various organs and of the whole organism.

Long covid is being researched by many scientists who are perturbed by the possibility of millions of cases of chronic debilitating sequelae following an apparently acute bout of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Much remains to be known about such long-term effects

Study: The effect of SARS-COV-2 Infections on Amyloid Formation of Serum Amyloid A. Image Credit: ChWeiss / Shutterstock

Amyloid significance

Serum amyloid A (SAA) is a marker of severe COVID-19, indicating overactive inflammatory immune responses and cytokine storms. SAA increases with the progression of the disease to a thousand-fold the baseline level in acute illness. Such abnormally high levels are characteristic of those with cancers or inflammatory diseases, who often have systemic amyloid deposition with its associated damage.

The SAA protein exists in different forms. The hexamer is the biologically active form that carries lipids around the body during inflammation. The monomers are prone to enzymatic cleavage, forming small fragments that form amyloid fibrils.

Amyloidosis induces inflammation, clot formation and injury to the tissue and organ. Kidney failure and clotting events are commonly seen in such patients.

The identity of symptomatology indicates the possibility that SAA deposition may underlie or worsen COVID-19 symptoms and may trigger long-term symptoms such as the multisystem inflammatory syndrome in children (MIS-C) and adults (MIS-A). This postulate spurred the current study, where molecular dynamics (MD) simulations are used to examine the relationship between the presence of the virus and SAA amyloids.

Amyloidosis is not observed in all cancerous or inflammatory conditions because of the cleavage of SAA hexamers after an initial SAA rise. The resultant drop in amyloid levels may be because such fragments are less likely to join up into functional hexamers compared to the complete SAA protein.

Secondly, the most common SAA1-76 fragment can switch between two structural motifs, one that rapidly breaks down, reducing SAA levels, but quick to aggregate, while the other is protected against proteolysis. The former will be predominant if amyloid formation is slower than amyloid breakdown.

In acidic conditions, which promote amyloid formation, the protected form is more abundant. This scenario, or any failure of SAA cleavage, results in amyloidosis. Such a failure might happen by SARS-CoV-2-induced destabilization of functional SAA hexamers; a higher chance of SAA fragment re-aggregation; or improved SAA fibril stability.

In any of these cases, SAA fibrils become more abundant.

The effect of SARS-CoV-2 on amyloid formation

The current computational study examined all three possibilities, with a particular focus on the effect of viral proteins rather than viral genetic material. The focus was on short sequences on the proteins that were likely to interact with SAA to form amyloid.

One such is the nine-residue SK9-segment on the envelope protein, which easily interacts with SAA. The homologous protein on SARS-CoV has been found to disrupt amylin aggregation.

Destabilization of the SAA hexamer

The researchers concluded that firstly, when SK9 bound to the SAA hexamer, it competitively inhibited the binding of the SAA protein chains among themselves, leading to reduced stability. This would promote monomer formation by hexamer disassembly.

This not only reduces the expression of SAA but promotes aggregation.

Secondly, when the hexamer dissociates, the monomers further break up into fragments for easier degradation into fibrils. The most commonly found fragment is SAA1-76. As this interacts with SK9, a new structure is formed.

This is called a beta-hairpin, involving several of the helix structures in the original fragment. This leads to the complete unfolding of one of them, helix II, and the fragment now becomes susceptible to easy proteolysis. This is called the helix-weakened form.

In the absence of SK9, the SAA1-76 form can change into the helix-broken form, which corresponds to the protected monomeric form. This is not affected by the viral segment.

Thus, the amyloidogenic SK9 sequence destabilizes the hexamer, shifting the distribution of the two forms of SAA1-76 towards the form that is readily aggregated. If the viral segment also destabilizes the two SAA motifs, it could increase the chances of SAA fibril formation.

The SK9 segment binds to the SAA fragment but then preferentially engages with hydrophobic and aromatic residues, as well as taking part in electrostatic interactions.

Fibril formation

At this point, the SAA monomer forms a beta-strand at the N-terminal end over the first 11 residues. This structure in this region is key to amyloid formation because fibril assembly begins here, with a beta-strand.

The tendency to form a beta-sheet in the helix-weakened SAA fragments, which are being preferentially formed in the presence of the viral segment, is a second impulse towards the amyloid formation.

Stabilization of amyloid fibrils

Thirdly, the SK9 segment encourages fibril stability. It binds to the outside of the SAA fragment SAA2-55, which are in the form of a two-fold-two-layer (2F2L) tetramer, this being the minimum size essential for fibril stability.

This indicates that indirect stabilization is occurring by increased stacking of chains. This takes place by preferential stacking hydrophobic interactions and hydrogen bonds at the cost of older packing interactions.

Packing distances between strands thus decrease while stacking is stabilized.

What are the conclusions?

The virus SARS-CoV-2 has secondary effects other than COVID-19, especially in the presence of some solid tumors or inflammatory conditions that predispose to amyloid deposition and its subsequent issues.

Nonetheless, high levels of SAA are not automatically associated with systemic amyloidosis due to the presence of protective mechanisms that reduce SAA concentrations. The current molecular dynamics simulation study shows three ways in which the virus bypasses these protections.

As a result, amyloidosis may underlie the many and varied inflammatory manifestations that make up MIS-C and MIS-A in COVID-19 survivors. Further research will show if fibril formation is part of the immune response in order to trap and neutralize the virus.

This possibility has been suggested with respect to herpes simplex, with the amyloidosis then becoming dominant to trigger Alzheimer’s disease. A similar process may be at work in SARS-CoV-2 infection, but this must be proved by future studies.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Jana, A. K. et al. (2021). The effect of SARS-COV-2 Infections on Amyloid Formation of Serum Amyloid A. bioRxiv preprint. doi: https://doi.org/10.1101/2021.05.18.444723, https://www.biorxiv.org/content/10.1101/2021.05.18.444723v1

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Tags: Amyloidosis, Children, Chronic, Coronavirus, Coronavirus Disease COVID-19, Cytokine, Flu, Genetic, Helix, Herpes, Herpes Simplex, Homologous, Immune Response, Inflammation, Kidney, Kidney Failure, Lipids, Pandemic, Protein, Research, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Virus

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Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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