BREAKING! Viral Peptide Fragments From SARS-Cov-2 Can Reassemble Into Proinflammatory Supramolecular Complexes!

COVID-19 News: In a groundbreaking discovery, researchers from prominent institutions, including the University of California, Los Angeles, the University of North Carolina at Chapel Hill, Harvard Medical School, and Stanford University, have unraveled a novel mechanism contributing to the severe inflammatory response observed in COVID-19 patients. The study explores how viral peptide fragments from SARS-CoV-2 can spontaneously reassemble into proinflammatory supramolecular complexes, shedding light on the diverse and often severe pathophysiological manifestations of the disease. This COVID-19 News report delves into the intricate details of the research, highlighting its significance in understanding the complexities of COVID-19.


Existence of exogenous mimics of pro-inflammatory host antimicrobial peptides (xenoAMPs) in SARS-CoV-2 proteins. (A) SARS-CoV-2 proteins are scanned with a machine learning AMP classifier. Each queried sequence is given a σ score that measures its AMP-ness. Three representative high-scoring sequences are studied: xenoAMP(ORF1ab), xenoAMP(S) and xenoAMP(M). The grey bars mark the location where the corresponding sequences are selected. (B) SARS-CoV-2 sequences are aligned and compared to their homologs in a common cold human coronavirus HCoV-OC43: Control (ORF1ab), Control(S) and Control(M). Asterisks, colons, and periods indicate positions that have fully conserved residues, those that have strongly similar properties, and those that have weakly similar properties, respectively. Color is assigned to each residue using the ClustalX scheme. (C) σ score heatmaps compare the distribution of high scoring sequences in three proteins from SARS-CoV-2 and HCoV-OC43. The first amino acid in each sequence is colored according to its average σ score; regions with negative average σ scores (non-AMPs) are colored white. “Hot spot” clusters of high-scoring sequences for SARS-CoV-2 (bright yellow regions bracketed in red boxes) have systematically higher scores and span wider regions of sequence space compared to HCoV-OC43. This trend suggests that hot spots in SARS-CoV-2 can generate higher scoring sequences for a greater diversity of enzymatic cleavage sites than those in HCoV-OC43.
 
Thailand Medical News has been warning about the presence of these viral peptides and also other peptides that are coded but not part of the RNA genomic structure but are possibly pathogenic as well since 2020, which some stupid scientists have been referring to as junk viral peptides!
 
https://www.thailandmedical.news/news/breaking-medical-news-discovery-of-hidden-viral-proteins-in-ssrna-viruses-opens-a-new-dimension-in-virology-and-is-relevant-for-sars-cov-2
 
https://www.thailandmedical.news/news/breaking-covid-19-news-australian-scientists-discover-a-microrna-called-cov2-mir-o8-that-is-encoded-by-sars-cov-2-and-is-possibly-pathogenetic
 
https://www.thailandmedical.news/news/breaking-covid-19-news-discovery-of-sars-cov-2-short-rnas-by-scientist-from-john-hopkins-is-a-big-gamechanger-in-terms-of-pathogenesis-and-long-covid
 
https://www.thailandmedical.news/news/breaking-news-scientists-discover-sars-cov-2-mirnas-that-contributes-to-pathogenesis-and-can-be-used-as-a-biomarker-for-covid-19-severity
 
https://www.thailandmedical.news/news/there-is-no-such-thing-as-long-covid-sars-cov-2-exposure-causes-persistent-infections-along-with-continuous-presence-of-short-viral-rnas-svrnas
 
https://www.thailandmedical.news/news/breaking-long-covid-is-a-misnomer-the-conditions-are-being-caused-by-viral-persistence-and-viral-peptides-similar-to-retrotransposons-and-introns
 
The Significance of the Study
The study addresses a critical gap in our understanding of the mechanistic underpinnings of severe inflammatory responses in COVID-19. While the infectious nature of SARS-CoV-2 is well-documented, this research emphasizes the virus's role not only as an infectious agent but also as a reservoir of replicated peptide motifs. These motifs, termed xenoAMPs, exhibit striking similarities to host antimicrobial peptides, particularly the cathelicidin LL-37. The researchers propose that these viral fragments, upon proteolytic degradation of the virus, can mimic host immune peptides and assemble with double-stranded RNA (dsRNA), resulting in proinflammatory nanocrystalline complexes.
 
Abstract Overview
The study introduces the perplexing question of how SARS-CoV-2 infection triggers a robust yet ineffective inflammatory response, affecting various cell types, including those without angiotensin-converting enzyme 2 receptors. The researchers explore the inflammatory capacity of viral fragments and identify sequence motifs resembling host antimicrobial peptides, especially LL-37. These xenoAMPs from SARS-CoV-2, unlike their harmless coronavirus homologs, can assemble dsRNA into nanocrystalline complexes, amplifying cytokine secretion in uninfected cells. The induced transcriptome closely mirrors the gene expression patterns observed in severe COVID-19 cases.
 
Pathophysiology of COVID-19
The study delves into the diverse pathophysiology of COVID-19, ranging from mild cases to severe respiratory failure, septic shock, and multisystem organ failure. The severe inflammatory response, characterized by elevated proinflammatory cytokines, particularly IL-6 and TNF-α, is discussed in the context of neutrophil infiltration, acute respiratory distress syndrome (ARDS), and extrapulmonary manifestations such as skin inflammation and coagulation pathologies. The study aims to connect these observations with the potential impact of SARS-CoV-2 xenoAMPs.
 
Exploring the Viral Proteome
The research proposes an unconventional approach by considering the viral proteome as a source of peptide fragments capable of imitating host antimicrobial peptides. Machine learning analysis identifies xenoAMP sequences in SARS-CoV-2 that exhibit high cationic charge and mimic the proinflammatory activity of cathelicidin LL-37. A comparison with common cold coronaviruses highlights the unique features of SARS-CoV-2 xenoAMPs, including their persistence and amplification in the host.
 
Proinflammatory Activity of XenoAMPs
The study presents compelling evidence of the proinflammatory activity of SARS-CoV-2 xenoAMPs. These viral fragments, selected based on their high cationic charge and machine learning scores, exhibit antimicrobial activity against bacterial strains. Furthermore, xenoAMPs can be generated during proteasomal degradation by specific proteases, including neutrophil elastase and matrix metalloproteinase-9, which are correlated with acute lung injury and hyperinflammation.
 
Comparison with Common Cold Coronaviruses
Comparisons between SARS-CoV-2 and common cold coronaviruses reveal distinct differences in the sequences and properties of xenoAMPs. The study demonstrates that SARS-CoV-2 has more sequences with high cationic charge and machine learning scores, suggesting an enhanced capacity for mimicking host AMPs. The higher transmissibility and replication kinetics of SARS-CoV-2 contribute to the abundance of xenoAMPs in COVID-19 patients.
 
Mass Spectrometry Insights
The researchers employ mass spectrometry to analyze tracheal aspirate samples from severe COVID-19 patients, detecting fragments of both host AMP LL-37 and SARS-CoV-2 peptides. The coexistence of these fragments in patient samples supports the hypothesis that viral xenoAMPs play a role in the observed inflammatory responses.
 
Discussion and Implications
The article delves into the implications of the study, emphasizing the potential connections between SARS-CoV-2 xenoAMPs, nucleic acids, and the diverse pathologies associated with COVID-19. The formation of complexes between viral fragments and nucleic acids is explored, providing insights into prolonged immune activation, aberrant TLR activation, and disrupted immune tolerance. The potential role of host proteases in generating xenoAMPs and the broader impact on COVID-19 pathogenesis are discussed, with suggestions for future research directions and potential therapeutic interventions.
 
Conclusion
In conclusion, this groundbreaking research unveils a previously unrecognized mechanism contributing to the severe inflammatory responses observed in COVID-19. The study highlights the role of SARS-CoV-2 viral fragments, termed xenoAMPs, in triggering proinflammatory nanocrystalline complexes. The findings provide a fresh perspective on the complexities of COVID-19 pathophysiology, linking viral proteome dynamics to diverse clinical manifestations. This knowledge opens avenues for further investigations and potential therapeutic interventions targeting the unique proinflammatory activity of SARS-CoV-2 xenoAMPs.
 
The study findings were published in the peer reviewed journal: Proceedings of the National Academy of Sciences (PNAS).
https://www.pnas.org/doi/10.1073/pnas.2300644120
 
For the latest COVID-19 News, keep on logging to Thailand Medical News.