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Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes | PNAS
▻https://www.pnas.org/doi/abs/10.1073/pnas.2300644120
▻https://www.pnas.org/cms/asset/e2e81613-f4a7-4700-ab95-679bd0354e48/keyimage.jpg
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.

Significance
At present, there are no criteria to evaluate whether a coronavirus can cause pandemics with severe inflammation or just common colds. We provide a possible answer by considering the virus not only as an infectious agent but as a reservoir of replicated peptide motifs that are not themselves pathogen associated molecular patterns (PAMPs) that specifically bind to pattern recognition receptors but are nevertheless capable of drastic immune amplification via self-assembly with PAMPs. We show evidence that viral peptide fragments from SARS-CoV-2 but not harmless coronavirus homologs can “reassemble” with dsRNA into a form of proinflammatory nanocrystalline condensed matter, resulting in cooperative, multivalent immune recognition and grossly amplified inflammatory responses.

Abstract
It is unclear how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to the strong but ineffective inflammatory response that characterizes severe Coronavirus disease 2019 (COVID-19), with amplified immune activation in diverse cell types, including cells without angiotensin-converting enzyme 2 receptors necessary for infection. Proteolytic degradation of SARS-CoV-2 virions is a milestone in host viral clearance, but the impact of remnant viral peptide fragments from high viral loads is not known. Here, we examine the inflammatory capacity of fragmented viral components from the perspective of supramolecular self-organization in the infected host environment. Interestingly, a machine learning analysis to SARS-CoV-2 proteome reveals sequence motifs that mimic host antimicrobial peptides (xenoAMPs), especially highly cationic human cathelicidin LL-37 capable of augmenting inflammation. Such xenoAMPs are strongly enriched in SARS-CoV-2 relative to low-pathogenicity coronaviruses. Moreover, xenoAMPs from SARS-CoV-2 but not low-pathogenicity homologs assemble double-stranded RNA (dsRNA) into nanocrystalline complexes with lattice constants commensurate with the steric size of Toll-like receptor (TLR)-3 and therefore capable of multivalent binding. Such complexes amplify cytokine secretion in diverse uninfected cell types in culture (epithelial cells, endothelial cells, keratinocytes, monocytes, and macrophages), similar to cathelicidin’s role in rheumatoid arthritis and lupus. The induced transcriptome matches well with the global gene expression pattern in COVID-19, despite using <0.3% of the viral proteome. Delivery of these complexes to uninfected mice boosts plasma interleukin-6 and CXCL1 levels as observed in COVID-19 patients.

Bringing a physicist’s mindset to the biosciences | UCLA
22/07/2022
▻https://newsroom.ucla.edu/stories/gerard-wong-brings-physicist-mindset-biosciences

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UCLA’s Gerard Wong approaches life sciences with an eye for connection and a distrust of metaphors
In his lab, Gerard Wong, professor of bioengineering at the UCLA Samueli School of Engineering, explores the molecular mechanisms behind basic processes of life and their influence on human health. But his original training was far afield — in physics, working with solids and liquids at the smallest scales.

That shift in scientific focus isn’t unprecedented, but the way Wong bridges the disparate disciplines is unusual. By applying not only instrumentation but also ideas from physics to biology, he has uncovered surprising links between the fields, which could have implications for bioscience and disease treatment.
[…]
For instance, one part of his current research program focuses on autoimmune diseases, which are typically viewed as a malfunction in a coordinated defense system. He aims to reveal how inflammation works at a more fundamental level, as a system that obeys physical laws.

“We imagine that the immune system recognizes something in a similar way to how we recognize something: This is DNA, this is RNA, this other thing is a part of the bacterial flagellum,” Wong said. “Nature might instead work through geometric shapes and sizes, entropy, interaction or lack of interaction with water, interactions between charged particles — in terms of the excruciatingly low-level, detailed, unifying language of physics.”

Taking this approach, the researchers revealed how certain molecules amp up the immune response, which can have applications to lupus, psoriasis, arthritis and other diseases.