Long covid
The effect of SARS-COV-2 Infections on Amyloid Formation of Serum Amyloid A
https://www.biorxiv.org/conten…/2021.05.18.444723v1.full
Abstract
A marker for the severeness and disease progress of COVID-19 is 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. Hence, in order to understand better the danger of SAA amyloidosis in the context of COVID-19 we have used molecular dynamic simulations to study the effect of a SARS-COV-2 protein segment on SAA amyloid formation. We find 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. Our results therefore suggest that SAA amyloidosis-related pathologies are a long-term risk of SARS-COV-2 infections.
Conclusions
The concentration of Human Serum Amyloid A (SAA) in acute COVID-19 patients can grow to levels that in patients with certain cancers or inflammatory diseases may cause systemic amyloidosis as a secondary illness. Hence, SARS-COV-2 infections may also increase the risk for SAA amyloid formation and subsequent pathologies. However, overexpression of SAA does not always lead to systemic amyloidosis, and mechanisms exist for downregulating SAA concentration and minimizing the risk for amyloidosis. In the present paper we use molecular dynamics to study how presence of SARS-COV-2 proteins may interfere with these protection mechanisms by changing the propensity for forming SAA amyloids. In order to reduce computational cost, we have restricted ourselves the nine-residue-segment S55FYVYSRVK63 (SK9) on the C-terminal tail of the SARS-COV2-Envelope protein whose location makes it likely to interact with SAA proteins.
Our simulations show that SARS-COV-2 proteins can increase the risk for SAA fibril formation by three mechanism. First, binding of the SK9 reduces the stability of the biologically active SAA hexamer in which SAA transports lipids during inflammation, shifting the equilibrium toward monomers. As monomers are SAA proteins subject to enzymatic cleavage into smaller fragments, and only these fragments are found in SAA fibrils. Hence, by shifting the equilibrium toward the monomers, presence of the viral protein segment SK9 increases the risk for fibril formation. This risk is further enhanced by the interaction of SK9 with the SAA fragments, which increase the frequency of the aggregation prone form (called by us helix-weakened) and for this motif raises the propensity to form β-strands, especially for the first eleven residues known to be crucial for fibril formation. Finally, presence of the amyloidogenic segment SK9 also stabilizes SAA fibrils, moving further the equilibrium toward the fibril, and therefore enhancing the probability for amyloid formation. Hence, our simulations strengthen our hypothesis that SARSCOV-2 infections raise the risk for SAA amyloidosis during or after COVID-19. As SAA amyloidosis is characterized by formation and deposition of SAA amyloids in the blood vessels, causing inflammation and thrombosis, it may be behind the broad spectrum of severe and at times lifethreatening cardiovascular, gastrointestinal, dermatologic, and neurological symptoms, commonly summarized as multisystem inflammatory syndrome (MISC) sometimes observed in COVID-19 survivors11.
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 hypothesis37,38 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.