Download PDF
CC BY-NC-ND 4.0 · J Lab Physicians 2023; 15(01): 056-061
DOI: 10.1055/s-0042-1750078
Original Article

SARS-CoV-2: The Self-Nonself Issue and Diagnostic Tests

Darja Kanduc 
1   Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, Bari, Italy
› Author Affiliations Funding None.
› Further Information
   Permissions and Reprints

Abstract

Objective At present, false negatives/positives have been reported in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostics. Searching for the molecular basis of such tests' unreliability, this study aimed at defining how specific are the sequences used in serological and polymerase chain reaction (PCR) tests to detect SARS-CoV-2.

Materials and Methods Analyses were performed on the leading SARS-CoV-2 biomarker spike glycoprotein (gp). Sharing of peptide sequences between the spike antigen and the human host was analyzed using the Peptide Search program from Uniprot database. Sharing of oligonucleotide sequences was investigated using the nucleotide Basic Local Alignment Search Tool (BLASTn) from National Center for Biotechnology Information (NCBI).

Results Two main points stand out: (1) a massive pentapeptide sharing exists between the spike gp and the human proteome, and only a limited number of pentapeptides (namely 107) identify SARS-CoV-2 spike gp as nonself when compared with the human proteome, and (2) the small phenetic difference practically disappears at the genetic level. Indeed, almost all of the 107 pentadecameric nucleotide sequences coding for the pentapeptides unique to SARS-CoV-2 spike gp are present in human nucleic acids too.

Conclusion The data are of immunological significance for defining the issue of the viral versus human specificity and likely explain the fact that false positives can occur in serological and PCR tests for SARS-CoV-2 detection.

Keywords

SARS-CoV-2 spike gp - self-nonself - serological tests - PCR tests - false positives


Publication History

Article published online:
26 July 2022

© 2022. The Indian Association of Laboratory Physicians. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

 

  • References

  • 1 Janeway Jr CA. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol Today 1992; 13 (01) 11-16
    CrossrefPubMedGoogle Scholar
  • 2 Rose NR. Negative selection, epitope mimicry and autoimmunity. Curr Opin Immunol 2017; 49: 51-55
    CrossrefPubMedGoogle Scholar
  • 3 Kanduc D. Immunobiology: on the inexistence of a negative selection process. Adv Stud Biol 2020; 12 (01) 19-28
    CrossrefGoogle Scholar
  • 4 Pradeu T, Carosella ED. On the definition of a criterion of immunogenicity. Proc Natl Acad Sci U S A 2006; 103 (47) 17858-17861
    CrossrefPubMedGoogle Scholar
  • 5 Kanduc D, Stufano A, Lucchese G, Kusalik A. Massive peptide sharing between viral and human proteomes. Peptides 2008; 29 (10) 1755-1766
    CrossrefPubMedGoogle Scholar
  • 6 Trost B, Lucchese G, Stufano A, Bickis M, Kusalik A, Kanduc D. No human protein is exempt from bacterial motifs, not even one. Self Nonself 2010; 1 (04) 328-334
    CrossrefPubMedGoogle Scholar
  • 7 Kanduc D. Peptide cross-reactivity: the original sin of vaccines. Front Biosci (Schol Ed) 2012; 4 (04) 1393-1401
    CrossrefPubMedGoogle Scholar
  • 8 Kanduc D. From anti-SARS-CoV-2 immune responses to COVID-19 via molecular mimicry. Antibodies (Basel) 2020; 9 (03) 33
    CrossrefPubMedGoogle Scholar
  • 9 Angileri F, Legare S, Marino Gammazza A, Conway de Macario E, Jl Macario A, Cappello F. Molecular mimicry may explain multi-organ damage in COVID-19. Autoimmun Rev 2020; 19 (08) 102591
    CrossrefPubMedGoogle Scholar
  • 10 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Lucchese G. Cerebrospinal fluid findings in COVID-19 indicate autoimmunity. Lancet Microbe 2020; 1 (06) e242
    CrossrefPubMedGoogle Scholar
  • 13 Landsteiner K, van der Scheer J. On the serological specificity of peptides. III. J Exp Med 1939; 69 (05) 705-719
    CrossrefPubMedGoogle Scholar
  • 14 Reddehase MJ, Rothbard JB, Koszinowski UH. A pentapeptide as minimal antigenic determinant for MHC class I-restricted T lymphocytes. Nature 1989; 337 (6208): 651-653
    CrossrefPubMedGoogle Scholar
  • 15 Endo M, Nunomura W, Takakuwa Y, Hatakeyama M, Higashi T. A novel epitope (pentapeptide) in the human hemoglobin beta chain. Hemoglobin 1998; 22 (04) 321-331
    CrossrefPubMedGoogle Scholar
  • 16 Tiwari R, Geliebter J, Lucchese A, Mittelman A, Kanduc D. Computational peptide dissection of Melan-a/MART-1 oncoprotein antigenicity. Peptides 2004; 25 (11) 1865-1871
    CrossrefPubMedGoogle Scholar
  • 17 Pieczenik G. Are the universes of antibodies and antigens symmetrical?. Reprod Biomed Online 2003; 6 (02) 154-156
    CrossrefPubMedGoogle Scholar
  • 18 Zeng W, Pagnon J, Jackson DC. The C-terminal pentapeptide of LHRH is a dominant B cell epitope with antigenic and biological function. Mol Immunol 2007; 44 (15) 3724-3731
    CrossrefPubMedGoogle Scholar
  • 19 Lucchese G, Stufano A, Trost B, Kusalik A, Kanduc D. Peptidology: short amino acid modules in cell biology and immunology. Amino Acids 2007; 33 (04) 703-707
    CrossrefPubMedGoogle Scholar
  • 20 Kanduc D. Homology, similarity, and identity in peptide epitope immunodefinition. J Pept Sci 2012; 18 (08) 487-494
    CrossrefPubMedGoogle Scholar
  • 21 Wu CH, Yeh LS, Huang H. et al. The protein information resource. Nucleic Acids Res 2003; 31 (01) 345-347
    CrossrefPubMedGoogle Scholar
  • 22 Altschul SF, Madden TL, Schäffer AA. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 1997; 25 (17) 3389-3402
    CrossrefPubMedGoogle Scholar
  • 23 Boratyn GM, Thierry-Mieg J, Thierry-Mieg D, Busby B, Madden TL. Magic-BLAST, an accurate RNA-seq aligner for long and short reads. BMC Bioinformatics 2019; 20 (01) 405
    CrossrefPubMedGoogle Scholar
  • 24 Bell PJ. The viral eukaryogenesis hypothesis: a key role for viruses in the emergence of eukaryotes from a prokaryotic world environment. Ann N Y Acad Sci 2009; 1178: 91-105
    CrossrefPubMedGoogle Scholar
  • 25 Koonin EV, Senkevich TG, Dolja VV. The ancient Virus World and evolution of cells. Biol Direct 2006; 1: 29
    CrossrefPubMedGoogle Scholar
  • 26 Kanduc D. The comparative biochemistry of viruses and humans: an evolutionary path towards autoimmunity. Biol Chem 2019; 400 (05) 629-638
    CrossrefPubMedGoogle Scholar
  • 27 Kanduc D, Lucchese A, Mittelman A. Non-redundant peptidomes from DAPs: towards “the vaccine”?. Autoimmun Rev 2007; 6 (05) 290-294
    CrossrefPubMedGoogle Scholar
  • 28 Kanduc D, Serpico R, Lucchese A, Shoenfeld Y. Correlating low-similarity peptide sequences and HIV B-cell epitopes. Autoimmun Rev 2008; 7 (04) 291-296
    CrossrefPubMedGoogle Scholar
  • 29 Lucchese A, Serpico R, Crincoli V, Shoenfeld Y, Kanduc D. Sequence uniqueness as a molecular signature of HIV-1-derived B-cell epitopes. Int J Immunopathol Pharmacol 2009; 22 (03) 639-646
    CrossrefPubMedGoogle Scholar
  • 30 Lucchese A, Guida A, Capone G, Petruzzi M, Lauritano D, Serpico R. Designing a peptide-based vaccine against Porphyromonas gingivalis. Front Biosci (Schol Ed) 2013; 5 (02) 631-637
    PubMedGoogle Scholar
  • 31 Kanduc D. Hydrophobicity and the physico-chemical basis of immunotolerance. Pathobiology 2020; 87 (04) 268-276
    CrossrefPubMedGoogle Scholar
  • 32 Kanduc D. The role of proteomics in defining autoimmunity. Expert Rev Proteomics 2021; 18 (03) 177-184
    CrossrefPubMedGoogle Scholar
  • 33 Patriquin G, Davidson RJ, Hatchette TF. et al. Generation of false-positive SARS-CoV-2 antigen results with testing conditions outside manufacturer recommendations: a scientific approach to pandemic misinformation. Microbiol Spectr 2021; 9 (02) e0068321
    CrossrefPubMedGoogle Scholar
  • 34 Benoit J, Benoit SW, Lippi G, Henry BM. False negative RT-PCR or false positive serological testing in SARS-CoV-2 diagnostics? Navigating between Scylla and Charybdis to prevent misclassification bias in COVID-19 clinical investigations. Diagnosis (Berl) 2020; 7 (04) 405-407
    CrossrefPubMedGoogle Scholar
  • 35 Verna R, Alallon W, Murakami M. et al. Analytical performance of COVID-19 detection methods (RT-PCR): scientific and societal concerns. Life (Basel) 2021; 11 (07) 660
    Google Scholar
  • 36 Corman VM, Landt O, Kaiser M. et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill 2020; 25 (03) 2000045
    CrossrefPubMedGoogle Scholar
  • 37 Surkova E, Nikolayevskyy V, Drobniewski F. False-positive COVID-19 results: hidden problems and costs. Lancet Respir Med 2020; 8 (12) 1167-1168
    CrossrefPubMedGoogle Scholar
  • 38 Braunstein GD, Schwartz L, Hymel P, Fielding J. False positive results with SARS-CoV-2 RT-PCR tests and how to evaluate a RT-PCR-positive test for the possibility of a false positive result. J Occup Environ Med 2021; 63 (03) e159-e162
    CrossrefPubMedGoogle Scholar
  • 39 Viswanathan M, Kahwati L, Jahn B. et al. Universal screening for SARS-CoV-2 infection: a rapid review. Cochrane Database Syst Rev 2020; 9: CD013718
    PubMedGoogle Scholar
  • 40 Gubbay JB, Rilkoff H, Kristjanson HL. et al. Impact of COVID-19 pre-test probability on positive predictive value of high cycle threshold SARS-CoV-2 real-time reverse transcription PCR test results. Infect Control Hosp Epidemiol 2021; 1: 18
    Google Scholar
  • 41 Kanduc D. Nucleotide sequence sharing between the human genome and primers for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection. Glob Med Genet 2022; 9 (02) 182-188
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Kanduc D. From Anti-SARS-CoV-2 immune response to the cytokine storm via molecular mimicry. Antibodies (Basel) 2021; 10 (04) 36
    CrossrefPubMedGoogle Scholar
  • 43 Churilov LP, Kanduc D, Ryabkova VA. COVID-19: adrenal response and molecular mimicry. Isr Med Assoc J 2021; 23 (10) 618-619
    PubMedGoogle Scholar
  • 44 Kanduc D. SARS-CoV-2-induced immunosuppression: a molecular mimicry syndrome. Glob Med Genet 2022
    Google Scholar
  • 45 Khavinson V, Terekhov A, Kormilets D, Maryanovich A. Homology between SARS CoV-2 and human proteins. Sci Rep 2021; 11 (01) 17199
    CrossrefPubMedGoogle Scholar