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DOI: 10.1055/s-0043-1761489
Molecular Mimicry between Respiratory Syncytial Virus F Antigen and the Human Proteome
Abstract
This study examined respiratory syncytial virus (RSV) F glycoprotein (gp) antigen for molecular mimicry with the human proteome. It was found that the viral antigen presents an impressive number of pentapeptides (namely, 525 out of 570) in common with the human proteome, with viral sequences widely and repeatedly distributed among 3,762 human proteins implicated in crucial fundamental cellular functions. The data can have implications for anti-RSV vaccines. Indeed, the high level of molecular mimicry can lead to cross-reactivity and autoimmunity, and invites to follow safer vaccinal protocols based on pentapeptide sequences uniquely present in the viral antigen.
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Introduction
Molecular mimicry, that is the sharing of sequences between pathogen and human proteins, is recently under intense investigation[1] [2] [3] to explain the thousands of adverse events associated with the anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination campaign.[4] Currently, as a few examples among the many, it has been documented that
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Antineuronal antibodies against brainstem antigens are associated with coronavirus disease 2019 (COVID-19)[5]
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COVID-19 induces autoantibodies against angiotensin II that correlate with blood pressure dysregulation and disease severity[6]
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Molecular mimicry is a prerequisite of autoimmunity following COVID-19.[7]
In general, the SARS-COV-2 data support and validate previous studies[8] [9] [10] [11] [12] according to which molecular mimicry and the consequent cross-reactivity represent the most likely pathogenic mechanism that leads to autoimmunity following vaccinations against infectious agents. Here, as a continuation of such studies, matching analyses have been extended to respiratory syncytial virus (RSV) F antigen and findings are described in [Table 1].
Number of human proteins involved in the sharing |
3,762 |
Viral pentapeptides occurring in the human proteome (including multiple occurrences) |
4,996 |
Number of pentapeptides composing the viral antigen |
5,70 |
Number of pentapeptides shared with the human proteome |
5,25 |
Abbreviation: RSV, respiratory syncytial virus.
a Pentapeptides were used as probes since a pentapeptide acts as a minimal determinant in humoral and cellular immune recognition.[13]
b The methodology for defining the pentapeptide sharing has been described in[11] [12] and utilized UniProt Peptide Search programs (www.uniprot.org).14–16 Analyses were performed on the primary sequence of RSV F gp, 574 amino acid long, Uniprot accession (AC) entry P03420.
Analysis of [Table 1] highlights three main points:
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1. First, the number of human proteins involved in the peptide sharing with the viral antigen is highest, that is 3,762. Moreover, many viral pentapeptides recur repeatedly among the 3,762 human proteins so that, including multiple occurrences, the total number of viral pentapeptides occurring in the human proteome is actually 4,996.
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2. Second, mathematically the massive dimensions of such viral versus human peptide sharing are unexpected. In fact, assuming that all amino acids occur with the same frequency, the probability of 1 pentapeptide occurring in two proteins is 1 out of 20[5] (or 1 in 3,200,000 or 0.0000003125). That is, it is close to zero.
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3. Third, only 45 out of the 570 viral pentapeptides are not shared with the human proteome, thus being unique to RSV F. They are in the order: VTFCF; TFCFA; YQSTC; RTGWY; TGWYT; GWYTS; NKCNG; KCNGT; YKNAV; MNYTL; KNYID; NKQSC; KQSCS; QQKNN; QKNNR; YMLTN; MPITN; GVIDT; DTPCW; TPCWK; CWKLH; WKLHT; PLCTT; LCTTN; GSNIC; TDRGW; DRGWY; RGWYC; GWYCD; YCDNA; QAETC; AETCK; VFCDT; EINLC; PKYDC; YDCKI; DCKIM; IVSCY; CYGKT; GCDYV; YVNKQ; HNVNA; TNIMI; YCKAR; NNIAF. Of note, a few unique viral pentapeptides overlap each other by four residues thus forming longer peptide stretches, that is, TDRGWYCD. Intriguingly, analysis of the Immune Epitope DataBase (IEDB, www.iedb.org) reveals that the octamer TDRGWYCD is present in the immunoreactive RSV F-derived epitope RTDRGWYCDNAGSVS (IEDB ID: 956694, with the octamer given underlined).[17]
Obvious space reasons prevent listing/discussing the 3,762 human proteins involved in the sharing and, as well, the multiple occurrences of the viral pentapeptides. Hence, data are given in [Supplemental Table S1], which is an essential part of this report to illustrate and infer the pathological potential of the peptide sharing. Indeed, for example, inspection of [Supplemental Table S1] (online only) shows that 29 coiled-coil domain-containing (CCDC) proteins are involved in the peptide sharing. CCDC proteins are implicated in numerous physiological and pathological processes like gametogenesis, embryonic development, hematopoiesis, angiogenesis, and ciliary development.[18] Then, it is evident that cross-reactivity with CCDC proteins alone would lead in itself to unrepairable damages to humans.
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Conclusions
The massive peptide commonality between RSV F antigen gp and the human proteome indicates and confirms a strict phenetic relationship between viruses and the origin of eukaryotic cells according to the endosymbiotic theory.[19] Such common evolutionary link can have a heavy immunological impact on and puts warns against using RSV F antigen or its oligopeptides in vaccinal compositions. Indeed, the highest extent of the peptide sharing between the viral antigen and human proteins and the consequent cross-reactive potential could cause collateral effects of unimaginable proportions both in number and in severity. In this regard, this report describes the 45 pentapeptide sequences unique to the RSV F antigen and absent in the human proteome, thus providing a molecular platform that can be used to formulate vaccines exempt of the cross-reactivity burden. De facto, using as an antigen the octamer TDRGWYCD described above, offers the possibility of formulating effective and safe immunotherapies for specifically hitting RSV.
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Conflicts of Interest
None declared.
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References
- 1 Sokolov AV, Isakova-Sivak IN, Mezhenskaya DA. et al. Molecular mimicry of the receptor-binding domain of the SARS-CoV-2 spike protein: from the interaction of spike-specific Abs with transferrin and lactoferrin to the antiviral effects of human recombinant 1. Biometals 2022; 1-26
- 2 Lucchese G, Flöel A. Molecular mimicry between SARS-CoV-2 and respiratory pacemaker neurons. Autoimmun Rev 2020; 19 (07) 102556
- 3 Kanduc D. SARS-CoV-2-induced immunosuppression: a molecular mimicry syndrome. Glob Med Genet 2022; 9 (03) 191-199
- 4 5.3.6 Cumulative analysis of post-authorization adverse event reports of Pf-07302048 (BNT162B2) received through 28-FEB-2021
- 5 Lucchese G, Vogelgesang A, Boesl F. et al. Anti-neuronal antibodies against brainstem antigens are associated with COVID-19. EBioMedicine 2022; 83: 104211
- 6 Briquez PS, Rouhani SJ, Yu J. et al. Severe COVID-19 induces autoantibodies against angiotensin II that correlate with blood pressure dysregulation and disease severity. Sci Adv 2022; 8 (40) eabn3777
- 7 Vahabi M, Ghazanfari T, Sepehrnia S. Molecular mimicry, hyperactive immune system, and SARS-COV-2 are three prerequisites of the autoimmune disease triangle following COVID-19 infection. Int Immunopharmacol 2022; 112: 109183
- 8 Kanduc D. Peptide cross-reactivity: the original sin of vaccines. Front Biosci (Schol Ed) 2012; 4 (04) 1393-1401
- 9 Kanduc D. Hydrophobicity and the physico-chemical basis of immunotolerance. Pathobiology 2020; 87 (04) 268-276
- 10 Kanduc D. The role of proteomics in defining autoimmunity. Expert Rev Proteomics 2021; 18 (03) 177-184
- 11 Kanduc D. From anti-severe acute respiratory syndrome coronavirus 2 immune response to cancer onset via molecular mimicry and cross-reactivity. Glob Med Genet 2021; 8 (04) 176-182
- 12 Kanduc D. Thromboses and hemostasis disorders associated with COVID-19: the possible causal role of cross-reactivity and immunological imprinting. Glob Med Genet 2021; 8 (04) 162-170
- 13 Kanduc D. Homology, similarity, and identity in peptide epitope immunodefinition. J Pept Sci 2012; 18 (08) 487-494
- 14 Chen C, Li Z, Huang H, Suzek BE, Wu CH. UniProt Consortium. A fast peptide match service for UniProt Knowledgebase. Bioinformatics 2013; 29 (21) 2808-2809
- 15 The UniProt Consortium. UniProt: the universal protein knowledgebase. Nucleic Acids Res 2017; 45 ( D1(: D158-D169
- 16 Chen C, Huang H, Wu CH. Protein bioinformatics databases and resources. Methods Mol Biol 2017; 1558: 3-39
- 17 Guvenel A, Jozwik A, Ascough S. et al. Epitope-specific airway-resident CD4+ T cell dynamics during experimental human RSV infection. J Clin Invest 2020; 130 (01) 523-538
- 18 Priyanka PP, Yenugu S. Coiled-coil domain-containing (CCDC) proteins: functional roles in general and male reproductive physiology. Reprod Sci 2021; 28 (10) 2725-2734
- 19 Kanduc D. The comparative biochemistry of viruses and humans: an evolutionary path towards autoimmunity. Biol Chem 2019; 400 (05) 629-638
Address for correspondence
Publication History
Article published online:
30 January 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Georg Thieme Verlag KG
Stuttgart · New York
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References
- 1 Sokolov AV, Isakova-Sivak IN, Mezhenskaya DA. et al. Molecular mimicry of the receptor-binding domain of the SARS-CoV-2 spike protein: from the interaction of spike-specific Abs with transferrin and lactoferrin to the antiviral effects of human recombinant 1. Biometals 2022; 1-26
- 2 Lucchese G, Flöel A. Molecular mimicry between SARS-CoV-2 and respiratory pacemaker neurons. Autoimmun Rev 2020; 19 (07) 102556
- 3 Kanduc D. SARS-CoV-2-induced immunosuppression: a molecular mimicry syndrome. Glob Med Genet 2022; 9 (03) 191-199
- 4 5.3.6 Cumulative analysis of post-authorization adverse event reports of Pf-07302048 (BNT162B2) received through 28-FEB-2021
- 5 Lucchese G, Vogelgesang A, Boesl F. et al. Anti-neuronal antibodies against brainstem antigens are associated with COVID-19. EBioMedicine 2022; 83: 104211
- 6 Briquez PS, Rouhani SJ, Yu J. et al. Severe COVID-19 induces autoantibodies against angiotensin II that correlate with blood pressure dysregulation and disease severity. Sci Adv 2022; 8 (40) eabn3777
- 7 Vahabi M, Ghazanfari T, Sepehrnia S. Molecular mimicry, hyperactive immune system, and SARS-COV-2 are three prerequisites of the autoimmune disease triangle following COVID-19 infection. Int Immunopharmacol 2022; 112: 109183
- 8 Kanduc D. Peptide cross-reactivity: the original sin of vaccines. Front Biosci (Schol Ed) 2012; 4 (04) 1393-1401
- 9 Kanduc D. Hydrophobicity and the physico-chemical basis of immunotolerance. Pathobiology 2020; 87 (04) 268-276
- 10 Kanduc D. The role of proteomics in defining autoimmunity. Expert Rev Proteomics 2021; 18 (03) 177-184
- 11 Kanduc D. From anti-severe acute respiratory syndrome coronavirus 2 immune response to cancer onset via molecular mimicry and cross-reactivity. Glob Med Genet 2021; 8 (04) 176-182
- 12 Kanduc D. Thromboses and hemostasis disorders associated with COVID-19: the possible causal role of cross-reactivity and immunological imprinting. Glob Med Genet 2021; 8 (04) 162-170
- 13 Kanduc D. Homology, similarity, and identity in peptide epitope immunodefinition. J Pept Sci 2012; 18 (08) 487-494
- 14 Chen C, Li Z, Huang H, Suzek BE, Wu CH. UniProt Consortium. A fast peptide match service for UniProt Knowledgebase. Bioinformatics 2013; 29 (21) 2808-2809
- 15 The UniProt Consortium. UniProt: the universal protein knowledgebase. Nucleic Acids Res 2017; 45 ( D1(: D158-D169
- 16 Chen C, Huang H, Wu CH. Protein bioinformatics databases and resources. Methods Mol Biol 2017; 1558: 3-39
- 17 Guvenel A, Jozwik A, Ascough S. et al. Epitope-specific airway-resident CD4+ T cell dynamics during experimental human RSV infection. J Clin Invest 2020; 130 (01) 523-538
- 18 Priyanka PP, Yenugu S. Coiled-coil domain-containing (CCDC) proteins: functional roles in general and male reproductive physiology. Reprod Sci 2021; 28 (10) 2725-2734
- 19 Kanduc D. The comparative biochemistry of viruses and humans: an evolutionary path towards autoimmunity. Biol Chem 2019; 400 (05) 629-638