Scientists Discover An Amyloidogenic Fragment In SARS CoV-2 Envelope Protein That Promotes Serum Amyloid A Misfolding And Fibrillization

COVID-19 News: The global impact of the COVID-19 pandemic has transcended the confines of a respiratory illness, unveiling a myriad of systemic effects associated with SARS-CoV-2 infection. Beyond the acute phase of the disease, a substantial fraction of patients experiences lingering symptoms termed post-acute sequelae or long-COVID, characterized by persistent neurological, respiratory, and inflammatory manifestations. This enduring impact necessitates a comprehensive understanding of the underlying molecular mechanisms driving these multi-organ effects, particularly focusing on the intricate interplay between viral components and host responses.


Amyloid fibril formation by SK9 peptide variants. Negative stain TEM images of (a) wild-type SK9 fibrils (magnification = 30000x), (b) SK9AA (magnification = 30000x), (c) SK9RA (magnification = 30000x) and (d) LV20 (magnification = 50000x). All peptides were incubated at 37 °C for two weeks prior to imaging.

Diverse Manifestations of SARS-CoV-2 Infection
The initial characterization of COVID-19 primarily emphasized respiratory distress and pneumonia. However, emerging evidence has highlighted the virus's ability to affect diverse organ systems, leading to complications such as abnormal blood coagulation, neurodegeneration, and cardiovascular disturbances. Notably, the neurological sequelae of COVID-19, ranging from cognitive impairment to neurological deficits, have garnered significant attention due to their persistent nature and potential long-term consequences.
 
Chronic Inflammation and Its Role in COVID-19 Complications
A key factor contributing to the wide-ranging impact of COVID-19 is the association with chronic inflammation, particularly in individuals with underlying health conditions like diabetes, obesity, or cardiovascular disease. This chronic inflammatory state is characterized by elevated levels of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α, creating a conducive environment for systemic complications and tissue damage. The sustained inflammatory response, even post-recovery from acute infection, underscores the complexity of COVID-19's pathophysiology and its implications for long-term health outcomes.
 
Serum Amyloid A (SAA) as a Marker of Inflammation and Amyloidosis
A crucial player in the inflammatory cascade is serum amyloid A (SAA), an acute phase protein synthesized in response to stress, infection, and tissue injury. While SAA plays a role in innate immunity and tissue repair during acute inflammation, persistent elevation of SAA levels, especially in chronic inflammatory conditions, can lead to its misfolding and aggregation, resulting in systemic AA amyloidosis. The correlation between increased SAA levels and COVID-19 severity further underscores the potential link between inflammation, amyloidosis, and viral pathogenesis.
 
Unraveling the Amyloidogenic Potential of SARS-CoV-2 Envelope Protein Peptide: SK9
The focal point of the study by the Hos pital for Sick Children-Toronto-Canada and the University of Toronto that is covered in this COVID-19 News report lies in deciphering the amyloidogenic properties of a specific peptide derived from the SARS-CoV-2 envelope protein, known as SK9 (54SFYVYSRVK62). This peptide, situated at the C-terminus of the viral envelope protein, was identified through computational algorithms predicting amyloid formation and molecular dynamics simulations.
 
Experimental Validation of SK9's Amyloidogenicity
Utilizing advanced techniques including Thioflavin T (ThT) fluorescence, circular dichroism (CD) spectroscopy, transmission electron microscopy (TEM), and peptide arrays, researchers conducted a rigorous examination of SK9's ability to form amyloid fibrils and interact with host proteins, particularly SAA. TEM images revealed the formation of amyloid-like aggregates of SK9, with distinct structural features indicative of amyloid fibrils. CD spectroscopy confirmed the disordered nature of SK9 in solution prior to fibril formation, emphasizing its transition to a β-sheet-rich conformation during amyloidogenesis.
 
Role of Aromatic Residues in SK9-Induced Amyloid Formation
A significant finding was the pivotal role played by aromatic residues, specifically Phe2 and Tyr3, in SK9's amyloidogenic function. Mutagenesis studies, substituting these aromatic residues with alanine in SK9AA, resulted in abolished fibrillization, highlighting the essentiality of aromatic interactions in stabilizing amyloid structures. Furthermore, a longer 20-residue fragment of the envelope protein, LV20, also exhibited amyloidogenic properties, suggesting the potential release of amyloidogenic peptides through proteolysis of the envelope protein in vivo.
 
Interactions Between SK9 and Serum Amyloid A (SAA)
The study elucidated the intricate molecular interactions between SK9 and SAA, shedding light on how viral peptides can influence host protein aggregation. SK9 was found to bind to specific amyloidogenic hotspots within SAA, particularly in helices 1 and 3, triggering SAA fibrillization in vitro. The binding affinity of SK9 to SAA was underscored by protease assays and peptide microarrays, revealing the protective effect of SK9 against trypsin digestion of SAA and the specific regions within SAA that interact with SK9.
 
Implications for COVID-19 Pathogenesis and Long-Term Complications
The findings from this study carry profound implications for understanding COVID-19 pathogenesis and its long-term consequences. By elucidating the mechanisms by which viral peptides like SK9 induce amyloid formation and interact with host proteins such as SAA, researchers have uncovered potential pathways contributing to systemic complications post-COVID-19 recovery. These pathways include the production of amyloidogenic peptides from viral proteins and the promotion of SAA aggregation, both fueled by the heightened inflammatory response characteristic of COVID-19.
 
Conclusion
In conclusion, the study provides a comprehensive exploration of the amyloidogenic properties of a specific peptide derived from the SARS-CoV-2 envelope protein and its interactions with host proteins like SAA. The intricate molecular mechanisms uncovered in this research offer valuable insights into the multi-organ effects of COVID-19 and the potential link between viral infection, chronic inflammation, and amyloidosis. Continued investigation in this realm holds promise for developing targeted therapeutic strategies to mitigate the long-term systemic complications associated with COVID-19 and improve patient outcomes.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2024.04.25.591137v1
 
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