Potential autoimmunity resulting from molecular mimicry between SARS-CoV-2 Spike and human proteins

Nunez-Castilla, Janelle; Stebliankin, Vitalii; Baral, Prabin; Balbin, Christian A.; Sobhan, Masrur; Cickovski, Trevor; Mondal, Ananda Mohan; Narasimhan, Giri; Chapagain, Prem; Mathee, Kalai; Siltberg-Liberles, Jessica

doi:10.1101/2021.08.10.455737

Cited by 14 publications

(13 citation statements)

References 86 publications

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“…A molecular mimicry map of SARS-CoV-2 was also generated [ 38 ], and earlier [ 39 ], autoimmune-linked MHC alleles (class I and class II) were published [ 38 , 40 , 41 , 42 , 43 , 44 ]. Emerging variants of concern, specifically the widespread Omicron variant, drew attention [ 45 , 46 , 47 ] without an Omicron-sourced autoimmunity focus, despite some literature with a broader or a different focus [ 48 , 49 , 50 ]. Changes in infectivity, prevention by vaccination, and other concerns [ 51 , 52 , 53 , 54 ], were of more interest.…”

Section: Introductionmentioning

confidence: 99%

Shared 6mer Peptides of Human and Omicron (21K and 21L) at SARS-CoV-2 Mutation Sites

Adıgüzel

Shoenfeld

2022

Antibodies

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We investigated the short sequences involving Omicron 21K and Omicron 21L variants to reveal any possible molecular mimicry-associated autoimmunity risks and changes in those. We first identified common 6mers of the viral and human protein sequences present for both the mutant (Omicron) and nonmutant (SARS-CoV-2) versions of the same viral sequence and then predicted the binding affinities of those sequences to the HLA supertype representatives. We evaluated change in the potential autoimmunity risk, through comparative assessment of the nonmutant and mutant viral sequences and their similar human peptides with common 6mers and affinities to the same HLA allele. This change is the lost and the new, or de novo, autoimmunity risk, associated with the mutations in the Omicron 21K and Omicron 21L variants. Accordingly, e.g., the affinity of virus-similar sequences of the Ig heavy chain junction regions shifted from the HLA-B*15:01 to the HLA-A*01:01 allele at the mutant sequences. Additionally, peptides of different human proteins sharing 6mers with SARS-CoV-2 proteins at the mutation sites of interest and with affinities to the HLA-B*07:02 allele, such as the respective SARS-CoV-2 sequences, were lost. Among all, any possible molecular mimicry-associated novel risk appeared to be prominent in HLA-A*24:02 and HLA-B*27:05 serotypes upon infection with Omicron 21L. Associated disease, pathway, and tissue expression data supported possible new risks for the HLA-B*27:05 and HLA-A*01:01 serotypes, while the risks for the HLA-B*07:02 serotypes could have been lost or diminished, and those for the HLA-A*03:01 serotypes could have been retained, for the individuals infected with Omicron variants under study. These are likely to affect the complications related to cross-reactions influencing the relevant HLA serotypes upon infection with Omicron 21K and Omicron 21L.

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Section: Introductionmentioning

confidence: 99%

Shared 6mer Peptides of Human and Omicron (21K and 21L) at SARS-CoV-2 Mutation Sites

Adıgüzel

Shoenfeld

2022

Antibodies

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“…Human TPO is a glycoprotein hormone that regulates the production of platelets, essential elements for blood coagulation (Kuter and Begley, 2002). Previously, we have shown that molecular mimicry between Spike and TPO may induce thrombocytopenia, a disorder with low blood platelet count (Nunez-Castilla et al ., 2021). The EMoMiS pipeline result provides further evidence that antibodies that recognize TQLPP in Spike may cross-react with TPO, causing the reduction of platelet counts.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular mimicry can also explain several unexpected side effects of the SARS-CoV-2 infection. We recently reported that molecular mimicry between SARS-CoV-2 Spike and human thrombopoietin (TPO) might induce thrombocytopenia in infected subjects (Nunez-Castilla et al ., 2021).…”

Section: Introductionmentioning

confidence: 99%

EMoMiS: A Pipeline for Epitope-based Molecular Mimicry Search in Protein Structures with Applications to SARS-CoV-2

Stebliankin

Baral

Balbin

et al. 2022

Preprint

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Epitope-based molecular mimicry occurs when an antibody cross-reacts with two different antigens due to structural and chemical similarities. Molecular mimicry between proteins from two viruses can lead to beneficial cross-protection when the antibodies produced by exposure to one also react with the other. On the other hand, mimicry between a protein from a pathogen and a human protein can lead to auto-immune disorders if the antibodies resulting from exposure to the virus end up interacting with host proteins. While cross-protection can suggest the possible reuse of vaccines developed for other pathogens, cross-reaction with host proteins may explain side effects. There are no computational tools available to date for a large-scale search of antibody cross-reactivity. We present a comprehensive Epitope-based Molecular Mimicry Search (EMoMiS) pipeline for computational molecular mimicry searches. EMoMiS, when applied to the SARS-CoV-2 Spike protein, identified eight examples of molecular mimicry with viral and human proteins. These findings provide possible explanations for (a) differential severity of COVID-19 caused by cross-protection due to prior vaccinations and/or exposure to other viruses, and (b) commonly seen COVID-19 side effects such as thrombocytopenia and thrombophilia. Our findings are supported by previously reported research but need validation with laboratory experiments. The developed pipeline is generic and can be applied to find mimicry for novel pathogens. It has applications in improving vaccine design. The developed Epitope-based Molecular Mimicry Search Pipeline (EMoMiS) is available from https://biorg.cs.fiu.edu/emomis/.

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“…Finally, the mRNA molecule is "humanized" by inserting 5' and 3' untranslated regions (UTRs) ) on its two ends, sequences borrowed from long-lasting human mRNAs, and adding a long poly-A tail to further promote resistance to breakdown [14]. The spike protein shares regions of high molecular similarity with many important human proteins, and molecular mimicry may lead to autoimmune disease, especially because the vaccine induces a very strong antibody response [17].…”

Section: Modifications In the Vaccine Mrna Sequencementioning

confidence: 99%

MAPK Activation, P53 and Autophagy Inhibition Characterize the SARS-CoV-2 Spike Protein Induced Neurotoxicity

Kyriakopoulos¹,

Nigh

McCullough³

et al. 2022

Preprint

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The SARS-CoV-2 spike protein and prions use common pathogenic pathways to induce toxicity in neurons. Infectious prions activate the p38 mitogen activated protein kinase (MAPK) pathway, and SARS-CoV-2 spike proteins induce the p38 MAPK and c-Jun NH2-terminal kinase (JNK) pathways through toll-like receptor signaling, indicating the potential for similar neurotoxicity, causing prion and prion-like disease. In this review we analyze the roles of autophagy inhibition, elevated intracellular p53 levels and reduced Wild-type p53-induced phosphatase 1 (Wip1) and dual-specificity phosphatase (DUSP) expression in neurons. The pathways induced by the spike protein via toll like receptor activation induce both PrP upregulation and β amyloid expression. Through the spike-protein-dependent elevation of p53 levels via β amyloid metabolism, increased PrP expression can lead to PrP misfolding and impaired autophagy, generating prion disease. We conclude that, according to the age of the spike protein-exposed patient and the state of their cellular autophagy activity, excess sustained activity of p53 in neurons may be a catalytic factor in neurodegeneration. We conclude that neurodegeneration is in part due to intensity and duration of spike protein exposure, patient age, cellular autophagy activity, and activation, function and regulation of p53. Finally, the neurologically damaging effects can be cumulatively spike-protein dependent, whether exposure is by natural infection or, more substantially, by repeated mRNA vaccination.

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Potential autoimmunity resulting from molecular mimicry between SARS-CoV-2 Spike and human proteins

Cited by 14 publications

References 86 publications

Shared 6mer Peptides of Human and Omicron (21K and 21L) at SARS-CoV-2 Mutation Sites

Shared 6mer Peptides of Human and Omicron (21K and 21L) at SARS-CoV-2 Mutation Sites

EMoMiS: A Pipeline for Epitope-based Molecular Mimicry Search in Protein Structures with Applications to SARS-CoV-2

MAPK Activation, P53 and Autophagy Inhibition Characterize the SARS-CoV-2 Spike Protein Induced Neurotoxicity

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