SARS-CoV-2 fragments increases inflammation by mimicking immune system peptides

Researchers have conducted an innovative study on the inflammatory capacity of fragmented components of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite extensive research during the COVID-19 pandemic, the factors that make the virus capable of triggering a dangerous inflammatory response remain unclear. A recent study published in the Journal of Proceedings of the National Academy of Sciences has revealed a novel mechanism involving amphiphilic, cationic peptides from the innate immune system that undergo amyloid-like assembly with anionic nucleic acids, forming pro-inflammatory complexes.

The study conducted by Zhang et al. aimed to determine whether fragmented SARS-CoV-2 peptides could assemble with anionic double-stranded RNA (dsRNA) to create supramolecular complexes. Using a support vector machine (SVM) classifier, the scientists identified potential antimicrobial peptide (AMP)-like sequences (xenoAMPs) within the SARS-CoV-2 proteome. Sequences with high cationic charges, particularly from the membrane (M) protein, spike (S) protein, and open reading frame 1ab (ORF1ab) polyprotein, were selected for further analysis. The researchers revealed that certain antimicrobial peptides (xenoAMPs) could be generated during the degradation of proteins by the proteasome. The study identified matrix metalloproteinase 9 (MMP9) and neutrophil elastase (NE) as potential generators of these xenoAMPs. The study compared these xenoAMPs with homologous sequences from SARS-CoV-1 and non-pandemic human CoVs and found partial conservation. Furthermore, fragments of host AMP cathelicidin LL-37 and viral peptide fragments were detected in tracheal aspirate samples from severe COVID-19 patients using mass spectrometry, which qualified as xenoAMPs with high σ scores.

The study also observed three xenoAMPs – xenoAMP(S), xenoAMP(M), and xenoAMP(ORF1ab) that were accompanied and assembled with dsRNA into complexes similar to LL-37. The researchers further investigated the robustness of these self-assembled proinflammatory complexes under non-optimal conditions. It was found that the nanocrystalline structures of these complexes were preserved when xenoAMPs were shortened. Co-crystallization with LL-37 suggested that host AMPs and xenoAMPs could synergistically activate inflammatory responses. Comparisons of the immune activation capacity of xenoAMPs from SARS-CoV-2 and homolog peptides from HCoV-OC43 were conducted using human monocytes.

Zhang and colleagues reported that xenoAMP-poly (I: C)-treated monocytes released 1.7-fold more interleukin (IL)-8 than controls, while HCoV-OC43 peptides induced much lower IL-8 levels. Primary human dermal microvascular endothelial cells (HDMVECs) treated with xenoAMP-poly (I: C) showed robust production of IL-6, which was not observed with HCoV-OC43 peptides. Finally, mice treated with xenoAMP(ORF1ab)-poly (I: C) complexes exhibited increased plasma levels of IL-6 and CXCL1 compared to controls, suggesting a potential role in inflammation propagation.

Researchers have explored a novel mechanism by which inflammation spreads in COVID-19. This discovery may offer insights into the similarities between the host immune system’s response in COVID-19 and individuals with autoimmune disorders. Understanding the heterogeneity of infection outcomes could pave the way for tailored approaches in managing COVID-19, with potential implications for individuals with autoimmune conditions.

Reference

Zhang Y, Bharathi V, Dokoshi T, de Anda J, Ursery LT, Kulkarni NN, et al. Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes. Proceedings of the National Academy of Sciences. 2024 Feb 6;121(6):e2300644120.

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