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Source: SARS-CoV-2 Research  May 24, 2021  28 days ago
BREAKING! University of Oklahoma Study Indicates That SARS-CoV-2 Might Cause Serum Amyloid A (SAA) Amyloidosis And Even Alzheimer Ultimately!
BREAKING! University of Oklahoma Study Indicates That SARS-CoV-2 Might Cause Serum Amyloid A (SAA) Amyloidosis And Even Alzheimer Ultimately!
Source: SARS-CoV-2 Research  May 24, 2021  28 days ago
A new study by researchers from University of Oklahoma has found that the SARS-CoV-2 coronavirus could be causing a secondary medical condition known as Serum Amyloid A (SAA)  Amyloidosis.

The proteins Serum amyloid A (SAA) are a family of apolipoproteins associated with high-density lipoprotein (HDL) in plasma. Different isoforms of SAA are expressed constitutively (constitutive SAAs) at different levels or in response to inflammatory stimuli (acute phase SAAs). These proteins are produced predominantly by the liver.
It is already known that acute-phase serum amyloid A proteins (A-SAAs) are secreted during the acute phase of inflammation. These proteins have several roles, including the transport of cholesterol to the liver for secretion into the bile, the recruitment of immune cells to inflammatory sites, and the induction of enzymes that degrade extracellular matrix.
A-SAAs are implicated in several chronic inflammatory diseases, such as amyloidosis, atherosclerosis, and rheumatoid arthritis. Three acute-phase SAA isoforms have been reported in mice, called SAA1, SAA2, and SAA3. During inflammation, SAA1 and SAA2 are expressed and induced principally in the liver, whereas SAA3 is induced in many distinct tissues. SAA1 and SAA2 genes are regulated in liver cells by the proinflammatory cytokines IL-1, IL-6, and TNF-α. Both SAA1 and SAA2 are induced up to a 1000-fold in mice under acute inflammatory conditions following exposure to bacterial lipopolysaccharide (LPS). Three A-SAA genes have also been identified in humans, although the third gene, SAA3, is believed to represent a pseudogene that does not generate messenger RNA or protein.
Serum amyloid A (SAA) is also an acute phase marker that responds rapidly. Similar to CRP, levels of acute-phase SAA increase within hours after inflammatory stimulus, and the magnitude of increase may be greater than that of CRP. Relatively trivial inflammatory stimuli can lead to SAA responses. It has been suggested that SAA levels correlate better with disease activity in early inflammatory joint disease than do ESR and CRP. Although largely produced by hepatocytes, more recent studies show that SAA is produced by adipocytes as well, and its serum concentration is associated with body mass index.
Importantly as a marker for the severeness and disease progress of COVID-19, overexpression of serum amyloid A (SAA) to levels that in other diseases are associated with a risk for SAA amyloidosis.
This secondary illness is characterized by formation and deposition of SAA amyloids in blood vessels, causing inflammation, thrombosis and sometimes organ failure, with symptoms resembling the multisystem inflammatory syndrome (MIS) observed in some COVID-19 survivors.
As such, in order to understand better the danger of SAA amyloidosis in the context of COVID-19 the study team had used molecular dynamic simulations to study the effect of a SARS-COV-2 protein segment on SAA amyloid formation.
 < ;br /> The study team found that presence of the nine-residue segment SK9, located on the Envelope protein, increases the propensity for SAA fibril formation by three mechanisms: it reduces the stability of the lipid-transporting hexamer shifting the equilibrium toward monomers, it increases the frequency of aggregation-prone configurations in the resulting chains, and it raises the stability of SAA fibrils.
The study findings therefore suggest that SAA amyloidosis-related pathologies are a long-term risk of SARS-COV-2 infections.
The study findings were published on a preprint server and are currently being peer reviewed.
It is interesting to speculate why amyloidogenic regions such as SK9 on SARS-COV-2 proteins seem to have such a pronounced effect on SAA amyloid formation. One possibility would be that fibril formation is part of the immune response and serves as a way to entrap and neutralize the virus. Such a microbial protection hypothesis has been suggest in context of Herpes Simplex I infections and the development of Alzheimer’s Disease.
Amyloid formation by SAA may serve a similar role, with SAA amyloidosis would be a consequence of this mechanism becoming overwhelmed. Further work will be needed to test this hypothesis
The 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.
This study findings describe 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.
Importantly 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
SAA or Serum amyloid A  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.
Typically such abnormally high levels are characteristic of those with cancers or inflammatory diseases, who often have systemic amyloid deposition with its associated damage.
It should be known that 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.
It is also already known that amyloidosis induces inflammation, clot formation and injury to the tissue and organ. Kidney failure and clotting events are commonly seen in such patients.
Significantly 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 this study, where molecular dynamics (MD) simulations are used to examine the relationship between the presence of the virus and SAA amyloids.
It should also be noted that 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.
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.
It has been found that 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.
This 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.
The study team 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.
Also 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.
Importantly 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.
Hence 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.
These SK9 segments bind to the SAA fragments but then preferentially engages with hydrophobic and aromatic residues, as well as taking part in electrostatic interactions. 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.
This 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.
Also 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.
The study concludes that the SARS-CoV-2 coronavirus 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.
However 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.
Hence 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.
Importantly this possibility has been suggested with respect to herpes simplex, with the amyloidosis then becoming dominant to trigger Alzheimer’s disease.
Alarmingly a similar process may be at work in SARS-CoV-2 infection, but further detailed studies are needed to verify this.
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