Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes, 2024, Zhang et al.

[SNT Gatchaman]

Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes
Zhang, Yue; Bharathi, Vanthana; Dokoshi, Tatsuya; de Anda, Jaime; Ursery, Lauryn Tumey; Kulkarni, Nikhil N.; Nakamura, Yoshiyuki; Chen, Jonathan; Luo, Elizabeth W. C.; Wang, Lamei; Xu, Hua; Coady, Alison; Zurich, Raymond; Lee, Michelle W.; Matsui, Tsutomu; Lee, HongKyu; Chan, Liana C.; Schepmoes, Athena A.; Lipton, Mary S.; Zhao, Rui; Adkins, Joshua N.; Clair, Geremy C.; Thurlow, Lance R.; Schisler, Jonathan C.; Wolfgang, Matthew C.; Hagan, Robert S.; Yeaman, Michael R.; Weiss, Thomas M.; Chen, Xinhua; Li, Melody M. H.; Nizet, Victor; Antoniak, Silvio; Mackman, Nigel; Gallo, Richard L.; Wong, Gerard C. L.

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.

Link | PDF (Proceedings of the National Academy of Sciences)

 

[SNT Gatchaman]

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.

 

[rvallee]

Getting a sense of cluster bombs here. Tiny code bombs executing pathogenic functions long after the mother bomb has fragmented. How weird to have insisted on "not a live virus" when viruses aren't even 'alive' and really just a bunch of proteins about which we still understand very little.

The arrogance of forcing mass reinfections without knowing about all the possible effects is stunning. Especially as the message about not bothering with respiratory infections has been applied by millions to other viruses, such as measles. As was predictable.

 

[SNT Gatchaman]

Background reference: Functional Reciprocity of Amyloids and Antimicrobial Peptides: Rethinking the Role of Supramolecular Assembly in Host Defense, Immune Activation, and Inflammation (2020, Frontiers in immunology)

 

[SNT Gatchaman]

Selected quotes from introduction —

Recent work has suggested that cationic, amphiphilic peptides from the innate immune system can undergo amyloid-like assembly with anionic nucleic acids into highly proinflammatory complexes. Here, we take an unusual approach and consider the proteome of a coronavirus as a reservoir of peptide fragments that can be liberated upon proteolytic destruction of the virions and assess the possibility that 1) such fragments can imitate host innate immune peptides and assemble with anionic dsRNA, a ligand common in viral infections and recognized by the innate immune system, and 2) whether the resultant assembled supramolecular complex can conceivably be related to the diverse pathophysiology of COVID-19.

In this work, we consider the possibility that proteolytic destruction of the virus by the immune system is not necessarily the endpoint for host viral clearance in COVID-19 [...]. We use a machine learning classifier to help identify immunomimetic peptide sequences in the SARS-CoV-2 proteome that recapitulate functions of cationic antimicrobial peptides (AMPs), a key class of effector molecules that can drive innate immune responses, the dysregulation of which can lead to autoimmune conditions such as lupus and rheumatoid arthritis.

Here, we show that immunomimetic cationic SARS-CoV-2 “xenoAMPs” can chaperone and organize anionic poly(I:C), a synthetic analog of dsRNA, into liquid crystalline complexes with lattice constants that are commensurate with the steric size of dsRNA receptor TLR3 [...] we show that xenoAMP-poly(I:C) complexes trigger strong cytokine secretion in a broad range of healthy, uninfected cells, including epithelial cells, endothelial cells, monocytes, and macrophages in culture.

These results suggest an unanticipated mechanism for severe COVID-19 derived pathologies such as cytokine storms, skin lesions, coagulation disorders, and significantly impact tissues that are not the direct target of infection.

 

[SNT Gatchaman]

Selected quotes from discussion —

We have shown that an unanticipated mechanism for propagating inflammation through uninfected cells exists for SARS-CoV-2 but not for common cold coronaviruses. This mechanism involves viral fragments able to mimic AMPs like LL-37 cathelicidin in host innate immunity. Given that LL-37 is involved in pathogenesis of lupus and rheumatoid arthritis, the notion that SARSCoV-2 peptide fragments can imitate LL-37 may be conceptually salient for understanding why the immune systems of COVID-19 patients resemble those of people with autoimmune disorders like lupus and rheumatoid arthritis.

The concept of COVID-19 propagation in the host via viral peptide fragments in addition to direct tissue infection creates many potential points of contact with existing observations. The formation of complexes between such peptides and nucleic acid is interesting from the perspective of hyperinflammation and autoimmune reactions.

Interestingly, proteolytic degradation of SARS-CoV-2 is likely to be heterogeneous, as individual hosts display distinctive patterns of enzyme efficiencies varying routinely by fourfold to 50-fold, with protein expression being “noisy” even at the single cell level. Stochastic transcription or alternative splicing of mRNA especially impacts environmentally responsive proteins (like proteases) with expression especially variable among genes of innate immunity. That proteolytic degradation of SARS-CoV-2 is expected to be drastically different among hosts may explain why the infection outcomes of SARS-CoV-2 are so heterogeneous, ranging from asymptomatic hosts to fatalities.

The formation of complexes between viral peptide fragments and nucleic acids can have longer-term consequences beyond acute inflammation since both the peptide and nucleic acid components are protected against enzymatic degradation in the host. What’s more, some of the xenoAMP sequences have some propensity to fold into either α-helical or β-sheet structures. Moreover, a recent study has shown that fragments from [neutrophil elastase] processed SARS-CoV-2 spike proteins can form amyloids, which in principle can contribute to greater longevity in vivo

It is possible that complex formation by SARS-CoV-2 xenoAMPs and nucleic acids can, at least in part, account for longer-term effects of COVID-19.

Results presented here indicate that there exist intrinsically proinflammatory sequences found in the SARS-CoV-2 proteome that are not found in common cold coronavirus homologs, sequences that strongly activate immune responses in a broad range of cell and tissue types connected to disease states in multiple systems. [...] It is quite possible that AMP-like viral fragments generated ectopically can be harmful, especially to vulnerable tissues such as the endothelium.

 

[SNT Gatchaman]

UCLA Newsroom: Viral protein fragments may unlock mystery behind serious COVID-19 outcomes

 

[Amw66]

And other viruses ?
May turn out to be very interesting.

 

[Sasha]

Any big brains on the forum care to speculate on the implications for ME/CFS, given that Lipkin and others did what seemed at the time to be a fairly conclusive ruling-out of PwME having more of any viruses in their bodies than controls? Could we have this peptide problem instead? Or has this possibly already been ruled out by ME/CFS research (which I haven't been following closely lately)?

@Simon M, @Jonathan Edwards ?

 

[Jonathan Edwards]

I doubt it means very much even in the context of acute Covid, @Sasha.

I cannot see any relevance to ME.

 

[Simon M]

Any big brains on the forum care to speculate on the implications for ME/CFS, given that Lipkin and others did what seemed at the time to be a fairly conclusive ruling-out of PwME having more of any viruses in their bodies than controls? Could we have this peptide problem instead? Or has this possibly already been ruled out by ME/CFS research (which I haven't been following closely lately)?

The studies were of viruses in either serum or plasma and didn't look at PBMCs (though you might expect infected PBMCs to shed viruses if the viruses were active) or other possible body reservoirs. Ideally, you would at least look for viruses in PBMCs.

Sorry, no idea about peptides or the findings in LC of viral RNA and any relevance ot MEcfs

 

[Ash]

Getting a sense of cluster bombs here. Tiny code bombs executing pathogenic functions long after the mother bomb has fragmented. How weird to have insisted on "not a live virus" when viruses aren't even 'alive' and really just a bunch of proteins about which we still understand very little.

The arrogance of forcing mass reinfections without knowing about all the possible effects is stunning. Especially as the message about not bothering with respiratory infections has been applied by millions to other viruses, such as measles. As was predictable.

The consequences are so grave that as things stand I think the rich are going achieve their goal of annihilating most of humanity, as this pandemic rolls on merging with other pathogens old and new.

 

[SNT Gatchaman]

Noting their reference to mmp-9 —

From our in silico prediction, NE and MMP-9 are both capable of generating xenoAMPs. In addition to direct damage to host tissue, up-regulated expression of NE and MMP-9 in critically ill COVID-19 patients can contribute to the proliferation of proinflammatory xenoAMPs.