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Original Article
15 (
1
); 56-61
doi:
10.1055/s-0042-1750078

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

Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, Bari, Italy
Address for correspondence: Darja Kanduc, PhD, Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, Bari 70125, Italy (e-mail: dkanduc@gmail.com).
Licence
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.
Disclaimer:
This article was originally published by Thieme Medical and Scientific Publishers Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.

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

Introduction

Canonical immunology lays on the concept that the human immune system evolved to attack and destroy extraneous entities such as infectious pathogens (that is, the “nonself”), in this way defending the human host (that is, the “self”) from harmful infections.[1] Accordingly, self-reactive lymphocytes that might react with peptides/structures present in the human host are selectively deleted from the immune repertoire to protect the host from self-reactivity.[1,2]

Hence, identification and mathematical definition of self and nonself entities are a conditio sine qua non for furthering our still incomplete understanding of the immune system,[3] exploiting the immunogenic potential of vaccines in fighting infectious agents, and formulating specific diagnostic tools.[4] Indeed, discriminating self from nonself currently is all the more necessary at the molecular level because in silico comparative sequence analyses[5,6] have documented that a high level of peptide sharing exists between pathogens and the human host. Immunologically, this peptide sharing highlights the risk that serological immunoassays for measuring patients' immune responses against a pathogen might actually reflect the extent of cross-reactivity phenomena targeting human proteins.[7]

In this scientific framework, taking the clue from recent data on the peptide sharing between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Homo sapiens,[8-12] the present study used SARS-CoV-2 spike glycoprotein (gp) as a research model and mathematically quantified the phenetic and genetic sequence differences that characterize the viral antigen as nonself when compared with the human host. That is, the entire human proteome was searched for peptide sequences shared with the viral gp. Pentapeptides were used as scanning probes to determine the exact viral versus human peptide sharing because a five amino acid grouping is the minimal antigenic and immunogenic space sufficient to specify an immune reaction, that is five amino acids represent the immune measurement unit.[13-20] Specifically, the research was addressed to find pentapeptide identities, i.e., perfect matches, between SARS-CoV-2 gp and human proteins. This is because for a perfect peptide match (i.e., 5/5 identities and no gaps allowed) there is one and only one corresponding nucleotide sequence while for a homologous peptide (i.e., a peptide where four out of five amino acids are identical but there is a gap) there would be more corresponding nucleotide sequences depending on the gap position.[20]

Following whole human proteome analyses, data were obtained showing that only a handful of pentapeptides (exactly 107 out of 1,269 pentapeptides) are uniquely present in the viral protein antigen and absent in the human host, in this way specifying the SARS-CoV-2 spike gp as nonself when compared with the human proteome. However, this phenetic difference disappears at the genetic level. Indeed, furthering at the nucleotide level the sequence analyses revealed that the pentadecameric oligonucleotides coding for the 107 pentapeptides present in the SARS-CoV-2 spike gp and not expressed in the human proteome actually are present in human nucleic acids too.

Materials and Methods

SARS-CoV-2 spike amino acid and nucleotide sequences were retrieved from isolate Wuhan-Hu-1, GenBank: MN908947.3. The viral protein antigen, which is 1,273 amino acids long, was dissected into 1,269 pentapeptides offset by 1 residue, that is, overlapped each other by 4 residues (i.e., MFVFL, FVFLV, VFLVL, and so forth). Next, for each viral pentapeptide, the entire human proteome was searched for occurrences of the same pentapeptide match by using PIR Peptide match (https://research.bioinformatics.udel.edu/peptidematch/index.jsp) and Peptide Search program (https://www.uniprot.org/peptidesearch/).[21]

Viral pentapeptides that are absent in the human proteome were further investigated at the genetic level using the nucleotide Basic Local Alignment Search Tool (BLASTn) program (http://blast.ncbi.nlm.nih.gov).[22,23] That is, for each pentapeptide unique to SARS-CoV-2 spike gp, the corresponding coding pentadecameric oligonucleotide sequence was used as a probe to scan the entire human NCBI (National Center for Biotechnology Information) nucleotide collection searching for instances of the same identical oligonucleotide sequence (i.e., 15/15 identities and no gaps allowed).

Results

SARS-CoV-2 Spike gp versus the Human Proteome: Self-Nonself at the Phenetic Level

Following PIR matching analyses of the SARS-CoV-2 spike gp versus the entire human proteome, the SARS-CoV-2 spike gp self could be defined as a set of 107 pentapeptide perfect matches. That is, only 107 out of 1,269 viral pentapeptides uniquely occur in the SARS-CoV-2 antigen and represent the molecular signature of the viral antigen, while the remaining 1,162 viral pentapeptides occur in the human proteome. Table 1 describes the pentapeptides unique to SARS-CoV-2 spike gp.

Table 1 SARS-CoV-2 spike gp pentapeptides that are absent in the human proteome
Posa Sequenceb Posa Sequenceb Posa Sequenceb Posa Sequenceb
34 RGVYY 230 PIGIN 538 CVNFN 901 MAYRF
35 GVYYP 257 GWTAG 617 CTEVP 904 RFNGI
36 VYYPD 264 AYYVG 651 IGAEH 1028 MSECV
37 YYPDK 280 NENGT 674 YQTQT 1045 GYHLM
61 NVTWF 297 SETKC 675 QTQTN 1046 YHLMS
62 VTWFH 311 GIYQT 693 IAYTM 1072 KNFTT
63 TWFHA 350 VYAWN 694 AYTMS 1078 PAICH
65 FHAIH 351 YAWNR 734 TSVDC 1097 NGTHW
85 PFNDG 361 CVADY 737 DCTMY 1098 GTHWF
101 IRGWI 375 STFKC 739 TMYIC 1099 THWFV
102 RGWIF 377 FKCYG 740 MYICG 1100 HWFVT
105 IFGTT 378 KCYGV 745 DSTEC 1101 WFVTQ
130 VCEFQ 379 CYGVS 759 FCTQL 1104 TQRNF
131 CEFQF 393 TNVYA 793 PIKDF 1107 NFYEP
132 EFQFC 418 IADYN 836 QYGDC 1129 IGIVN
136 CNDPF 420 DYNYK 837 YGDCL 1134 NTVYD
143 VYYHK 421 YNYKL 838 GDCLG 1209 IKWPW
148 NNKSW 433 VIAWN 848 DLICA 1210 KWPWY
149 NKSWM 435 AWNSN 849 LICAQ 1211 WPWYI
152 WMESE 436 WNSNN 850 ICAQK 1214 YIWLG
153 MESEF 477 STPCN 851 CAQKF 1215 IWLGF
160 YSSAN 479 PCNGV 868 MIAQY 1224 IAIVM
166 CTFEY 485 GFNCY 883 SGWTF 1233 LCCMT
184 GNFKN 486 FNCYF 885 WTFGA 1234 CCMTS
199 GYFKI 493 QSYGF 897 FAMQM 1236 MTSCC
203 IYSKH 534 VKNKC 899 MQMAY 1253 CCKFD
204 YSKHT 536 NKCVN 900 QMAYR

a Position along the SARS-CoV-2 spike gp.

b Amino acid sequence in one-letter code.

Hence, a first datum provided from this study is that serological tests to measure the extent of the antiviral immune response might equate mostly to measuring the immune response against proteins of the human host.

SARS-CoV-2 Spike Gene versus the Human Genome: Self-Nonself at the Genetic Level

As a second step, the 107 pentapeptides that are absent in the human proteome and uniquely present in the spike gp were controlled at the genetic level for oligonucleotide sharing. The scientific rationale at the basis of such control analyses is the following. If the absence of the 107 pentapeptides described in Table 1 marks and differentiates the viral gp antigen from the human proteome, as a logical consequence such an absence must exist at the nucleic acid level too, by being nucleic acids the ultimate repository of the information that specifies and identifies proteins and organisms.

On that account, human nucleic acids were searched for oligonucleotide sequences coding for the SARS-CoV-2 spike gp pentapeptides not expressed in the human proteome. The results obtained by using the BLASTn program are illustrated in Table 2 that shows that practically all pentadecameric oligonucleotide sequences corresponding to the unique 107 SARS-CoV-2 spike gp pentapeptides occur and often repeatedly recur in coding and/or noncoding human nucleic acids. Exception is the pentapeptide YSSAN (amino acid position: 160–164), the corresponding oligonucleotide of which was repeatedly found at the 13mer level.

Table 2 Occurrences in human nucleic acids of the pentadecameric oligonucleotides coding the 107 pentapeptides uniquely present in SARS-CoV-2 spike gp
Pentapeptidea 5′-Oligodeoxynucleotide-3′b,c Occurrences in human nucleic acids
Plus strand Minus strand
RGVYY CGTGGTGTTTATTAC 1 1
GVYYP GGTGTTTATTACCCT 4
VYYPD GTTTATTACCCTGAC 2
YYPDK TATTACCCTGACAAA 13 4
NVTWF AATGTTACTTGGTTC 7 7
VTWFH GTTACTTGGTTCCAT 5 11
TWFHA ACTTGGTTCCATGCT 12 14
FHAIH TTCCATGCTATACAT 13 9
PFNDG CCATTTAATGATGGT 8 12
IRGWI ATAAGAGGCTGGATT 3 7
RGWIF AGAGGCTGGATTTTT 41 59
IFGTT ATTTTTGGTACTACT 13 11
VCEFQ GTCTGTGAATTTCAA 15 21
CEFQF TGTGAATTTCAATTT 46 64
EFQFC GAATTTCAATTTTGT 46 43
CNDPF TGTAATGATCCATTT 20 21
VYYHK GTTTATTACCACAAA 17 19
NNKSW AACAACAAAAGTTGG 18 19
NKSWM AACAAAAGTTGGATG 22 31
WMESE TGGATGGAAAGTGAG 29 25
MESEF ATGGAAAGTGAGTTC 6 19
YSSAN TATTCTAGTGCGAAT
CTFEY TGCACTTTTGAATAT 2 7
GNFKN GGTAATTTCAAAAAT 30 45
GYFKI GGTTATTTTAAAATA 54 71
IYSKH ATATATTCTAAGCAC 18 30
YSKHT TATTCTAAGCACACG 5 2
PIGIN CCAATAGGTATTAAC 4 20
GWTAG GGTTGGACAGCTGGT 5 11
AYYVG GCTTATTATGTGGGT 18 21
NENGT AATGAAAATGGAACC 28 10
SETKC TCAGAAACAAAGTGT 21 27
GIYQT GGAATCTATCAAACT 3 10
VYAWN GTTTATGCTTGGAAC 2 2
YAWNR TATGCTTGGAACAGG 5 8
CVADY TGTGTTGCTGATTAT 10 15
STFKC TCCACTTTTAAGTGT 19 17
FKCYG TTTAAGTGTTATGGA 13 15
KCYGV AAGTGTTATGGAGTG 2 1
CYGVS TGTTATGGAGTGTCT 2
TNVYA ACTAATGTCTATGCA 5 6
IADYN ATTGCTGATTATAAT 44 43
DYNYK GATTATAATTATAAA 63 46
YNYKL TATAATTATAAATTA 71 82
VIAWN GTTATAGCTTGGAAT 6 13
AWNSN GCTTGGAATTCTAAC 17 4
WNSNN TGGAATTCTAACAAT 15 23
STPCN AGCACACCTTGTAAT 7 6
PCNGV CCTTGTAATGGTGTT 9 4
GFNCY GGTTTTAATTGTTAC 10 13
FNCYF TTTAATTGTTACTTT 50 29
QSYGF CAATCATATGGTTTC 10 27
VKNKC GTTAAAAACAAATGT 35 56
NKCVN AAAAACAAATGTGTC 19 44
CVNFN TGTGTCAATTTCAAC 60 42
CTEVP TGCACAGAAGTCCCT 21 9
IGAEH ATAGGGGCTGAACAT 1 3
YQTQT TATCAGACTCAGACT 37 21
QTQTN CAGACTCAGACTAAT 9 7
IAYTM ATTGCCTACACTATG 1 4
AYTMS GCCTACACTATGTCA 1 1
TSVDC ACATCAGTAGATTGT 12 8
DCTMY GATTGTACAATGTAC 1
TMYIC ACAATGTACATTTGT 18 32
MYICG ATGTACATTTGTGGT 13 21
DSTEC GATTCAACTGAATGC 1 2
FCTQL TTTTGTACACAATTA 9 12
PIKDF CCAATTAAAGATTTT 26 22
QYGDC CAATATGGTGATTGC 1
YGDCL TATGGTGATTGCCTT 3
GDCLG GGTGATTGCCTTGGT 3 5
DLICA GACCTCATTTGTGCA 5 2
LICAQ CTCATTTGTGCACAA 6 12
ICAQK ATTTGTGCACAAAAG 19 37
CAQKF TGTGCACAAAAGTTT 23 19
MIAQY ATGATTGCTCAATAC 1 5
SGWTF TCTGGTTGGACCTTT 53 42
WTFGA TGGACCTTTGGTGCA 1
FAMQM TTTGCTATGCAAATG 26 15
MQMAY ATGCAAATGGCTTAT 5 9
QMAYR CAAATGGCTTATAGG 4 1
MAYRF ATGGCTTATAGGTTT 9 10
RFNGI AGGTTTAATGGTATT 1 5
MSECV ATGTCAGAGTGTGTA 6 6
GYHLM GGCTATCATCTTATG 1
YHLMS TATCATCTTATGTCC 4
KNFTT AAGAACTTCACAACT 5 8
PAICH CCTGCCATTTGTCAT 17 13
NGTHW AATGGCACACACTGG 14 11
GTHWF GGCACACACTGGTTT 4 11
THWFV ACACACTGGTTTGTA 5 4
HWFVT CACTGGTTTGTAACA 5 5
WFVTQ TGGTTTGTAACACAA 52 54
TQRNF ACACAAAGGAATTTT 47 62
NFYEP AATTTTTATGAACCA 22 35
IGIVN ATAGGAATTGTCAAC 3 1
NTVYD AACACAGTTTATGAT 15 15
IKWPW ATAAAATGGCCATGG 27 25
KWPWY AAATGGCCATGGTAC 5 3
WPWYI TGGCCATGGTACATT 12 5
YIWLG TACATTTGGCTAGGT 2 4
IWLGF ATTTGGCTAGGTTTT 18 14
IAIVM ATTGCCATAGTAATG 9 5
LCCMT CTTTGCTGTATGACC 4 14
CCMTS TGCTGTATGACCAGT 2 6
MTSCC ATGACCAGTTGCTGT 11 2
CCKFD TGCTGCAAATTTGAT 11 21

a Pentapeptides uniquely present in SARS-CoV-2 spike gp when compared with the human proteome.

b Oligodeoxynucleotide sequences coding for pentapeptides unique to SARS-CoV-2 spike gp.

c Each pentadecameric oligodeoxynucleotide sequence was used as a probe to scan the entire human NCBI nucleotide collection for exact 15/15 identities with no gaps allowed, using BLASTn program.[22,23] Further data and details are available at http://blast.ncbi.nlm.nih.gov.

Discussion

This study analyzes the pentapeptide sharing between SARS-CoV-2 spike gp and the human proteome, and mathematically defines the identity of the viral antigen as a set of 107 pentapeptides uniquely present in the spike gp and absent in the human proteins. Crucially, this viral versus human phenetic specificity disappears at the genetic level. The data have relevant implications in SARS-CoV-2 immunology, vaccinology, and clinical diagnostics.

Indeed, in the immunological context described under Introduction, the presence in human nucleic acids of the oligonucleotide sequences coding for the 107 pentapeptides that phenetically specify the viral antigen fails to support the deterministic hypothesis according to which the immune system evolved to discriminate infectious nonself from noninfectious self.[1-3] Rather, Tables 1 and 2 suggest that SARS-CoV-2 and humans derived their genetic information from common ancestral templates. In this regard, this study supports the viral eukaryogenesis hypothesis, according to which the primordial eukaryotic cell was a consortium consisting of a viral ancestor of the nucleus, an archaeal ancestor of the eukaryotic cytoplasm, and a bacterial ancestor of mitochondria.[24-26]

Moreover, the present data confirm and strengthen the concept[27-32] that only vaccine formulations based on peptide sequences uniquely present in infectious pathogens and absent in the host proteins have the potential to selectively hit the pathogens and halt infections. In the case in point, by being absent in the human proteome, the unique SARS-CoV-2 spike gp peptides described in Table 1 represent an ideal basic peptidome platform that could result in effective and highly specific anti-SARS-CoV-2 vaccines exempt from harmful cross-reactivity.

Clinically and of utmost importance in diagnostics, the viral versus human pentapeptide and oligonucleotide sharing shown in Table 1 and 2, respectively, could have a severe impact on the validity of the current polymerase chain reaction (PCR) tests for SARS-CoV-2 spike detection. In fact, claims have been reported about the rates of false negatives/positives in SARS-CoV-2 detection by means of serological and PCR tests,[33-38] in this way raising numerous concerns. As observed by Viswanathan et al,[39] healthy individuals may be falsely identified as positive, requiring confirmatory testing and potentially leading to the unnecessary isolation of these individuals. In agreement, Gubbay et al[40] suggested that large-scale SARS-CoV-2 screening testing initiatives among low pretest probability populations should be evaluated thoroughly prior to implementation given the risk of false positives and consequent potential for harm at the individual and population levels, and this not to mention the enormous waste of economic resources that might be caused by unreliable large-scale SARS-CoV-2 tests. As a matter of fact, data from Table 1 clearly suggest that serological immunoassays for measuring antipathogen antibody response might actually be indicative of cross-reactions with human proteins. In line with Table 1, Table 2 indicates that SARS-CoV-2 spike detection by PCR might be affected by the risk that human nucleotide sequences can be amplified, thus generating false-positive results with consequent wrong medical diagnoses. Such a risk is real in light of the fact that oligonucleotide sequences have been shown to be shared between the human genome and primers that have been proposed/used for SARS-CoV-2 detection by PCR.[41] Therefore, this study might be of help not only to understand cross-reactivity phenomena and to address new specific peptide-based approaches in anti-SARS-CoV-2 vaccinal protocols but also to define a specific and precise diagnostics of SARS-CoV-2 infection and disease.

In closing, it is also worth noting that, in agreement with reports from this laboratory,[8,10,11,42-44] Khavinson et al[45] have recently described an intense peptide sharing between almost all the SARS-CoV-2 proteins and human proteins, with hepta- and octamers scattered along the entire length of the SARS-CoV-2 spike protein molecule, thus furtherly supporting the possibility of cross-reactivity and consequent autoimmunity between SARS-CoV-2 and the human host.[7]

Conflicts of Interest

None declared.

Funding

None.

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