Understanding SARS-CoV-2-induced systemic amyloidosis

Understanding SARS-CoV-2-induced
systemic amyloidosis
By Tarun Sai Lomte Dec 21 2021
Reviewed by Aimee Molineux

In a recent analysis, researchers investigated the formation of amyloid fibrils in

coronavirus disease 2019 (COVID-19) patients and posted their results to the
bioRxiv* preprint server.

The world is witnessing a massive surge in severe acute respiratory syndrome

coronavirus 2 (SARS-CoV-2) cases with over 270 million reported cases to date.
Several coronaviruses (OC43, 229E, NL63, HKU1) are known to infect humans
causing respiratory disorders; however, COVID-19 has been found to affect
multiple organ systems causing extra-respiratory tract complications such as
heart failure, peripheral neuropathy, central nervous system (CNS) disorders,
and blood coagulation.

Study: Amyloidogenesis of SARS-CoV-2 Spike Protein. Image Credit: Dotted

Yeti/Shutterstock

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The study
In the present study, researchers investigated if the SARS-CoV-2 S protein
could cause amyloidosis. Coronaviruses use their surface spike (S) protein to
attach with host cells. About 316 spike peptides (15-mers with 11 amino acid
[aa] overlap) were screened initially in two equal sub-pools and assayed in vitro
for amyloid fibril formation.

Further, they generated 20 aa peptide sequences to find the most

amyloidogenic sequences by using the WALTZ prediction algorithm. The
peptides were lyophilized and dissolved in hexafluoroisopropanol (HFIP),
followed by dilution in PBS buffer. They were maintained at a concentration of
0.1 mg/ml (10% HFIP) and observed for the formation of amyloid fibrils in
vitro. The formation kinetics was monitored using Thioflavin T (ThT), Congo red
birefringence (CR), and negative stain transmission electron microscopy (TEM).

Findings
The team discovered seven synthetic (amyloidogenic) peptides which were 20
amino acids in length within the S protein and found that six of them were in
beta-sheet conformation as observed in the cryo-EM structure of SARS-CoV-2 S
protein in its closed state. It was noted that these peptides in isolation could
aggregate as fibrils at 37°C during incubation. Of these seven peptides, three
peptides were found to meet the criteria of amyloid fibrils: sigmoid ThT kinetics,
congophilicity, and ultrastructural fibrillar morphology. These peptides were
Spike191, Spike532, and Spike1165, which are named according to the starting
position of the S-protein.

Further, the researchers analyzed the fibril formation with these seven peptides
as a mixture resulting in sigmoidal ThT kinetics based on a nucleation-
dependent mechanism and noticed that the fibril morphology was similar to that
of Spike191 indicating that this peptide was dominant in the mixture.

It is known that proteolysis of precursor proteins initiates amyloid formation in

several diseases like Alzheimer’s disease, British and Danish dementia, and
Finnish amyloidosis. The S protein of SARS-CoV-2 is also reported to be
proteolyzed in hosts as an immune response and therefore, to understand the
plausible mechanism of fibril formation, the full-length S protein was cleaved in
vitro by using the enzyme, neutrophil elastase (NE). NE, secreted by

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Understanding SARS-CoV-2-induced systemic amyloidosis

neutrophils, was selected after positive results of in silico proteolysis of S

protein were obtained. The analysis revealed that full-length S protein can not
form fibrils and neither could NE alone; however, co-incubation of the two
proteins formed fibrils indicative of proteolytic cleavage by NE that resulted in a
Spike191-like peptide.

Conclusion
The findings reported in the study provide an understanding of amyloidosis
observed in COVID-19 patients. COVID-19 induces multifactorial and complex
pathogenesis like acute respiratory distress syndrome (ARDS) from several
inflammatory reactions of the innate immune system. Cytokine storm, cardiac,
neural, and renal damage have also been reported due to COVID-19.

Several studies observed blood coagulation in COVID-19 patients due to

aggregation of extracellular amyloid fibrils.

Furthermore, it has been reported that NE is overexpressed at sites of

inflammation and vaccine administration. Globally, over eight billion COVID-19
vaccine doses have been administered so far and a majority of them are mRNA-
based vaccines that deliver information to encode the SARS-CoV-2 S protein as
the main antigen. Recently, the formation of fibrils was noted in a human at the
site of mRNA-vaccine injection and in lymph nodes within 24 hours of
administration.

The findings observed that endoproteolysis of S protein by NE, which generates

peptides such as 193-202 segment, and possibly other amyloidogenic segments
by other proteases could form amyloid fibrils. Complications like fibrinolysis,
blood clotting, cerebral amyloid angiopathy, FXII Kallikrein/Kinin activation, and
thromboinflammation have been linked with amyloidosis which could suggest a
possible link between COVID-19 phenotypes and amyloidogenesis of S-protein.

In conclusion, the authors proposed that inflammation combined with

aggregates of amyloidogenic peptides of SARS-CoV-2 S proteins might induce
systemic amyloidosis.

*Important notice
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and,

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Understanding SARS-CoV-2-induced systemic amyloidosis

therefore, should not be regarded as conclusive, guide clinical practice/health-

related behavior, or treated as established information.

Journal reference:
Sofie Nyström, Per Hammarström. (2021). Amyloidogenesis of SARS-CoV-
2 Spike Protein. bioRxiv. doi: https://doi.org/10.1101/2021.12.16.472920
https://www.biorxiv.org/content/10.1101/2021.12.16.472920v1

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in
Biotechnology from the University of Hyderabad and is enthusiastic about scientific
research. He enjoys reading research papers and literature reviews and is passionate
about writing.

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