CC BY 4.0 · Glob Med Genet 2021; 08(04): 176-182
DOI: 10.1055/s-0041-1735590
Original Article

From Anti-Severe Acute Respiratory Syndrome Coronavirus 2 Immune Response to Cancer Onset via Molecular Mimicry and Cross-Reactivity

1  Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, Bari, Italy
› Author Affiliations
Funding None.
 

Abstract

Background and Objectives Whether exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may predispose to the risk of cancer in individuals with no prior cancers is a crucial question that remains unclear. To confirm/refute possible relationships between exposure to the virus and ex novo insurgence of tumors, this study analyzed molecular mimicry and the related cross-reactive potential between SARS-CoV-2 spike glycoprotein (gp) antigen and human tumor-suppressor proteins.

Materials and Methods Tumor-associated proteins were retrieved from UniProt database and analyzed for pentapeptide sharing with SARS-CoV-2 spike gp by using publicly available databases.

Results An impressively high level of molecular mimicry exists between SARS-CoV-2 spike gp and tumor-associated proteins. Numerically, 294 tumor-suppressor proteins share 308 pentapeptides with the viral antigen. Crucially, the shared peptides have a relevant immunologic potential by repeatedly occurring in experimentally validated epitopes. Such immunologic potential is of further relevancy in that most of the shared peptides are also present in infectious pathogens to which, in general, human population has already been exposed, thus indicating the possibility of immunologic imprint phenomena.

Conclusion This article described a vast peptide overlap between SARS-CoV-2 spike gp and tumor-suppressor proteins, and supports autoimmune cross-reactivity as a potential mechanism underlying prospective cancer insurgence following exposure to SARS-CoV-2. Clinically, the findings call for close surveillance of tumor sequelae that possibly could result from the current coronavirus pandemic.


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Introduction

From lung damages to skin diseases and excessive immune responses, the disorders associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that is, coronavirus disease 2019 (COVID-19), are progressively being defined and diagnostically cataloged.[1] [2] [3] [4] [5] [6] [7] Among the many diseases encompassed by COVID-19, clinical attention has focused on the relationship between SARS-CoV-2 and cancer.[8] [9] [10] Indeed, when compared with the pre-COVID-19 era, COVID-19 pandemic appears to be characterized by higher hospitalization and mortality rates in prostate cancer patients[11]; increased breast cancer dimensions[12]; increased proportion of patients with advanced non-small cell lung cancer[13]; and a higher number of diagnosed head and neck cancers (2.9–8.06% in January–April 2020).[14] Such data have been interpreted as due to the pressure exerted by the viral pandemic on the health care system, so cancer treatments have been delayed and, also, have been related to the viral infection per se.[15] However, how SARS-CoV-2 infection might relate to cancer diseases remains unclear.

According to the research paradigm that peptide sequences common to pathogens and the human host may lead to autoimmunity through cross-reactivity,[16] [17] [18] [19] [20] [21] a previous report[22] has proposed cross-reactivity as a likely mechanism that can explain the immunopathology related to SARS-CoV-2 exposure. As a matter of fact, many SARS-CoV-2-derived epitopes were shown to share peptide sequences with human proteins that are involved—when altered, mutated, deficient, and/or improperly functioning—in the etiology of the diseases encompassed by COVID-19.[22] Moreover, and of special importance, it was noted that the viral versus human peptide sharing also involved human proteins related to pleuropulmonary blastoma, non-small cell lung cancer, breast invasive ductal carcinoma, multiple human cancers, tumor predisposition syndrome, and mesothelioma, inter alia. That is, the data suggested the possibility that morbidity/mortality increases in various tumors might represent long-term sequelae following exposure to SARS-CoV-2 (Kanduc[22] and pertinent references therein).

Hence, this study was undertaken to further explore the relationship between SARS-CoV-2 infection/active immunization and carcinogenesis, and specifically focused on the amino acid (aa) sequence identities between SARS-CoV-2 spike glycoprotein (gp) and tumor-suppressor human proteins. Analyses revealed a vast peptide sharing potentially able to generate pathogenic autoantibodies via cross-reactivity and immunologic imprinting phenomena, thus possibly leading to or enhancing the onset of a wide spectrum of cancer diseases.


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Materials and Methods

Peptide sharing between SARS-CoV-2 spike gp (NCBI, GenBank Protein Accession ID = QHD43416.1) and cancer-related human proteins was analyzed using pentapeptides as sequence probes as already described.[16] [17] [18] [19] [20] [21] [22] Pentapeptides were used as minimal immune determinant units since a peptide grouping formed of five aa residues defines an immune unit that can (1) induce highly specific antibodies and (2) determine antigen–antibody-specific interaction (Kanduc[23] [24] and further references therein). Seven hundred eighty-two human proteins (in)directly linked to cancer were obtained from UniProtKB database (www.uniprot.org)[25] using “tumor suppressor” as keywords and are listed by UniProt entry in [Supplementary Table S1] (available in online version only).

Methodologically, the spike gp primary sequence was dissected into pentapeptides offset by one residue (i.e., MFVFL, FVFLV, VFLVL, FLVLL, and so forth) and the resulting viral pentapeptides were analyzed for occurrences within the human proteins related to cancer. The shared peptides were also controlled for occurrences in the pathogens Bordetella pertussis, Corynebacterium diphtheriae, Clostridium tetani, Haemophilus influenzae, and Neisseria meningitides. The publicly available peptide match and peptide search programs (www.uniprot.org) were used.[25]

The immunologic potential of the peptides shared between SARS-CoV-2 spike gp and cancer-related proteins was investigated by searching the Immune Epitope Database (IEDB, www.iedb.org)[26] for experimentally validated immunoreactive SARS-CoV-2 spike gp-derived epitopes hosting the shared pentapeptides.


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Results and Discussion

Searching UniProt database for tumor-suppressor proteins produced 782 protein entries (in)directly related to tumor-suppressor activity and listed in [Supplementary Table S1] (available in online version only). Of the 782 proteins, 294 have pentapeptides in common with the spike gp, in a total of 308 occurrences (in all, 462, including multiple occurrences). These numbers certify the existence of an impressive, unexpected level of molecular mimicry between the viral antigen and the cancer-related human proteins. Obvious reasons of space prevent a detailed analysis peptide-by-peptide of the peptide overlap that is given in its entirety in [Supplementary Table S2] (available in online version only). Here in text, a snapshot of the peptide sharing is reported and discussed.

Peptide Sharing between SARS-CoV-2 Spike gp and Tumor-Suppressor Proteins

[Table 1] shows data relative to a representative sample of 19 tumor-suppressor proteins and documents that the peptide commonality with the viral antigen amounts to 29 pentapeptides. From a pathological perspective, [Table 1] clearly illustrates that even hitting only 19 out of the 294 tumor-suppressor proteins described in [Supplementary Table S2] (available in online version only) might equate to induce or enhance carcinogenesis in almost all of the human organs, from brain and liver to lung and bones. Examples of the cancers that might be evoked/potentiated by exposure to SARS-CoV-2 in the next future are T cell acute lymphoblastic leukemia, oligodendrogliomas, breast/ovarian cancers, sarcoma, malignant mesothelioma, B cell chronic lymphocytic leukemia, and non-small cell lung carcinoma, among the others.

Table 1

Peptide sharing between SARS-CoV-2 spike gp and a representative sample of 19 tumor-suppressor proteins

Shared peptides

Tumor-suppressor proteins and related cancer diseases[a]

Refs[b]

DPFLG

BC11B. B cell lymphoma/leukemia 11B. T cell acute lymphoblastic leukemia

 [27] [28]

LPPLL, GAGAA, QDVVN, SPDVD

BICRA. Glioma tumor suppressor candidate. Oligodendrogliomas

 [29]

EPQII

BRCA1. Breast cancer type 1 susceptibility protein. Breast/ovarian cancer

 [30]

SLGAE, LAATK, EPVLK

BRCA2. Breast cancer type 2 susceptibility protein. Breast cancer

 [31]

RVVVL

DCC. Netrin receptor DCC. Deleted in colorectal carcinoma. Gallbladder cancer

 [32]

YRVVV, SALGK

DIRA1. GTP-binding protein Di-Ras1. Small GTP-binding tumor suppressor 1. Lost/downregulated in neural tumors

 [33]

ITDAV

EXT1. Exostosin-1. Putative tumor suppressor protein EXT1. Bone tumors

 [34]

ALLAG

EXT2. Exostosin-2. Putative tumor suppressor protein EXT2. Bone tumors

 [34]

TLKSF, RLQSL

IL24. Interleukin-24. Suppression of tumorigenicity 16 protein. Melanoma

 [35] [36]

SKPSK

LATS1. Large tumor suppressor homolog 1. Soft tissue sarcoma.

 [37]

ARDLI

LATS2. Large tumor suppressor homolog 2. Malignant mesothelioma

 [38]

YSNNS

MTUS1. Microtubule-associated tumor suppressor 1. Hepatocellular carcinoma

 [39]

GAGAA

PLAT2. Phospholipase A and acyltransferase 2. Gastric cancer

 [40]

GAGAA

PLAT3. Phospholipase A and acyltransferase 3. Ovarian carcinoma cells

 [41]

ADAGF, TYVPA

RBM5. Putative tumor suppressor LUCA15. Lung cancer

 [42]

RDLPQ, NSVAY

SCAI. Suppressor of cancer cell invasion. Downregulated in human tumors

 [43]

LLTDE

SDS3. Suppressor of defective silencing 3 protein homolog. Antitumor activity

 [44]

TQSLL, NFKNL, AGAAA

TASOR. Transcription activation suppressor. Clear cell renal cell carcinoma

 [45]

LSRLD, GDSSS

TRI13. B cell chronic lymphocytic leukemia tumor suppressor Leu5. B cell chronic lymphocytic leukemia. Non-small cell lung carcinoma

 [46] [47]

Abbreviations: gp, glycoprotein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.


a Tumor-suppressor proteins given by UniProt entry are in italic.


b Further references on cancer diseases are available at UniProt, OMIM, and PubMed.



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Immunologic Potential of the Peptide Sharing between SARS-CoV-2 Spike gp and Tumor-Suppressor Proteins

The gloomy outlook hinted at by the findings described in [Table 1] becomes all the more likely in light of the high immunologic potential of the shared peptides. De facto, investigation of IEDB shows that the 29 pentapeptides shared by the spike gp antigen and the 19 tumor-suppressor proteins ([Table 1]) occur and recur in 150 epitopes derived from SARS-CoV-2 that have been experimentally validated and are cataloged as immunoreactive ([Table 2]).

Table 2

Immunoreactive SARS-CoV-2 spike gp-derived epitopes containing peptides shared between SARS-CoV-2 spike gp and tumor-suppressor human proteins

IEDB ID[a]

Epitope sequence[b]

IEDB ID[a]

Epitope sequence[b]

36724

litgRLQSL

1329082

ADAGFikqygdclgdia

38831

lQDVVNqnaqalntl

1329083

ADAGFikqygdclgdiaa

51999

qpYRVVVLsf

1329254

demiaqytsALLAG

54725

RLQSLqtyv

1329256

demiaqytsALLAGt

533447

raaeirasanLAATK

1329258

demiaqytsALLAGti

1069290

cTLKSFtvekgiyqt

1329260

demiaqytsALLAGtit

1069445

EPQIIttdntfvsgn

1329323

efqfcnDPFLGvyy

1073938

vqidrlitgRLQSLq

1329325

efqfcnDPFLGvyyh

1074928

ilpdpSKPSK

1329327

efqfcnDPFLGvyyhk

1125063

gltvLPPLL

1329329

efqfcnDPFLGvyyhkn

1309132

nfsqilpdpSKPSKr

1329342

emiaqytsALLAG

1309418

aeirasanLAATKmsecvlg

1329344

emiaqytsALLAGt

1309447

dfggfnfsqilpdpSKPSKr

1329345

emiaqytsALLAGtit

1309450

dplsetkcTLKSFtvekgiy

1329353

EPQIIttdntfvsg

1309451

dsfkeeldkyfknhtSPDVD

1329390

fcnDPFLGvyyh

1309467

fdeddsEPVLKgvklhyt

1329414

fqfcnDPFLGvyy

1309478

gNFKNLrefvfknidgyfki

1329416

fqfcnDPFLGvyyh

1309482

gyqpYRVVVLsfellhapat

1329422

fsqilpdpSKPSKr

1309515

lhrsyltpGDSSSgwtagaa

1329571

idrlitgRLQSLq

1309516

litgRLQSLqtyvtqqlira

1329572

idrlitgRLQSLqt

1309519

lpdpSKPSKrsfiedllfnk

1329595

iqdslsstaSALGKlq

1309523

lssnfgaissvlndiLSRLD

1329597

iraaeirasanLAATK

1309532

ngltvLPPLLTDEmiaqyts

1329606

ITDAVdcaldplse

1309534

nitrfqTLLALhrsyltpgd

1329627

khtpinlvRDLPQg

1309546

pflmdlegkqgNFKNLrefv

1329659

lADAGFikqygdclgdiaa

1309556

qfcnDPFLGvyyhknnkswm

1329710

lpdpSKPSKrsfiedllfnkvt

1309561

qrnfyEPQIIttdntfvsgn

1329762

miaqytsALLAG

1309566

qygdclgdiaARDLIcaqkf

1329764

miaqytsALLAGt

1309567

RDLPQgfsaleplvdlpigi

1329793

ndiLSRLDkveaevq

1309585

sssgwtAGAAAyyvgylqpr

1329940

qidrlitgRLQSLqt

1309589

sygfqptngvgyqpYRVVVL

1329966

qpYRVVVLsfellhapa

1309593

tITDAVdcaldplsetkctl

1329969

qsiiaytmSLGAE

1309599

TYVPAqeknfttapaichdg

1329978

raaeirasanLAATKm

1309605

vsngthwfvtqrnfyEPQII

1330138

staSALGKlQDVVN

1310254

aeNSVAYSNNSiaip

1330167

tdemiaqytsALLAGt

1310284

ARDLIcaqkfngltv

1330169

tdemiaqytsALLAGti

1310303

caqkfngltvLPPLL

1330171

tdemiaqytsALLAGtit

1310362

eldkyfknhtSPDVD

1330209

TLKSFtvekgiyqts

1310392

fgttldskTQSLLiv

1330210

TLKSFtvekgiyqtsn

1310415

fngltvLPPLLTDEm

1330211

TLKSFtvekgiyqtsnf

1310448

gklQDVVNqnaqaln

1330219

tpGDSSSgwtAGAAA

1310586

litgRLQSLqtyvtq

1330220

tpinlvRDLPQg

1310609

lpdpSKPSKrsfied

1330305

vqidrlitgRLQSLqt

1310611

LPPLLTDEmiaqyts

1330306

vqidrlitgRLQSLqtyv

1310747

qpYRVVVLsfellha

1330368

yfkiyskhtpinlvRDLPQ

1310750

qrnfyEPQIIttdnt

1330391

ytsALLAGtit

1310847

titsgwtfGAGAAlq

1330433

diLSRLD

1310947

wtfGAGAAlqipfam

1330434

diLSRLDppeaevq

1311657

ccscgscckfdeddsEPVLKgvkl

1330437

dslsstaSALGKl

1311782

pdpSKPSKrsfiedllfnkvtlad

1330438

dslsstaSALGKlq

1312257

cckfdeddsEPVLKg

1330439

dslsstaSALGKlqdv

1312283

deddsEPVLKgvklh

1330447

EPQIIttdntfvsgnc

1312733

ilpdpSKPSKrsfie

1330456

fsqilpdpSKPSK

1312780

ITDAVdcaldplset

1330457

fsqilpdpSKPSKrs

1313154

miaqytsALLAGtit

1330463

gfnfsqilpdpSKPSKr

1313286

pinlvRDLPQgfwal

1330487

ilpdpSKPSKr

1313756

TLKSFtvek

1330489

iqdslsstaSALGKl

1313930

vTYVPAqeknfttap

1330490

iqdslsstaSALGKlqd

1314170

ADAGFikqy

1330515

lADAGFikqy

1315180

aYSNNSiai

1330551

pSKPSKrsf

1316068

etkcTLKSF

1330552

pSKPSKrsfi

1316945

fsqilpdpSKPSKrsfie

1330557

qilpdpSKPSKr

1318209

hvTYVPAqek

1330589

slsstaSALGKlq

1320443

lgaeNSVAY

1330597

sqilpdpSKPSK

1321084

LPPLLTDEm

1330598

sqilpdpSKPSKr

1323467

qpYRVVVL

1330623

tpinlvRDLPQgfs

1323750

rasanLAATK

1330624

tpinlvRDLPQgfsa

1323919

RLQSLqty

1330625

tpinlvRDLPQgfsalepl

1324353

setkcTLKSF

1331139

cnDPFLGvy

1325536

tlADAGFik

1332424

itgRLQSLqty

1327824

wtAGAAAyy

1332664

LLTDEmiaqy

1327836

wtfGAGAAl

1334122

TYVPAqeknft

1328800

ytmslgaeNSVAY

1334394

yqpYRVVVL

1328800

ytmSLGAEnsvay

1334452

alhrsyltpGDSSSg

1329076

aaeirasanLAATK

1334473

NSVAYSNNSiaiptnft

Abbreviations: gp, glycoprotein; IEDB, Immune Epitope Database; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.


a Epitopes listed according to the IEDB ID number.


b Shared sequences given are capitalized.


In essence, [Table 2] factually supports the possibility that cross-reactions can be triggered by SARS-CoV-2 infection/active immunization and hit human proteins related to carcinogenesis. Very much this conclusion applies when considering that the extent of the potential immunologic cross-reactivity as well as the spectrum of potentially inducible tumors may be exponentially higher in light of the fact that [Tables 1] and [2] refer to the peptide commonality involving only a tiny part (19 out of 294) of the human proteins that—if altered—may lead to cancer (see [Supplementary Table S2] [available in online version only] for the peptide sharing in its totality).


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Potential Immunologic Imprint

The 29 pentapeptides common to SARS-CoV-2 spike gp and tumor-suppressor proteins ([Table 1]) are not only present in immunoreactive epitopes ([Table 2]) but, in addition, almost all of them (24 out of 29) are also present in microbial organisms such as Bordetella pertussis, C. diphtheriae, C. tetani, H. influenzae, and N. meningitides ([Table 3]). That is, most of the shared peptides are also present in pathogens that an individual possibly encountered during his life because of infections and/or vaccinal routes.

Table 3

Occurrences in microbial organisms of pentapeptides common to SARS-CoV-2 spike gp, human proteins related to cancer, and SARS-CoV-2 spike gp-derived epitopes

Organism

Shared peptides

Bordetella pertussis

ADAGF, AGAAA, ALLAG, GAGAA, ITDAV, RLQSL, SLGAE, SPDVD, TYVPA

Clostridium tetani

AGAAA, LAATK, LLTDE, YSNNS

Corynebacterium diphtheriae

AGAAA, ALLAG, EPQII, GAGAA, ITDAV, SALGK, YRVVV

Haemophilus influenzae

AGAAA, GAGAA, LLTDE, LPPLL, LSRLD, NFKNL, NSVAY, RDLPQ, RLQSL, RVVVL, SALGK, SLGAE, TLKSF, TQSLL, YSNNS

Neisseria meningitides

AGAAA, ALLAG, EPVLK, GAGAA, LLTDE, LPPLL

Abbreviations: gp, glycoprotein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.


Such interpathogen peptide commonality introduces the immunologic memory as a factor capable of enhancing the extent of the immune cross-reactive response against the tumor-suppressor proteins. That is, as already described since 1947,[48] [49] the immune system does not induce ex novo primary responses toward a recent infection. Rather, the immune system recalls, amplifies, and intensifies preexisting memory responses toward past infections. In this way, what should have been a primary response to a recent infection is transformed into an anamnestic, secondary, and magnified response to past infections. Simply put, as already discussed in previous reports,[50] [51] [52] [53] [54] [55] the early history of the individual's infections/vaccinations dictates the immune outcomes of any successive infections/vaccinations.

The immunologic imprint phenomenon has its molecular foundations in the massive peptide sharing that characterizes microbial and human proteins[17] [56] [57] and of which [Table 3] is an example. The implications are noteworthy. In the case object, following exposure to SARS-CoV-2 by infection or vaccination, the expected primary response to the virus can turn into a secondary response to previously encountered pathogens against which the immune system already reacted and of which has stored an immunologic memory, that is, the microbial organisms reported in [Table 3]. However, the previously encountered pathogens are no more present in the human organism, so that the anamnestic immune response triggered by the exposure to SARS-CoV-2 by infection or vaccination ends to divert onto available immune determinants that, in the present case, are the common determinants present in the tumor-suppressor human proteins. Pathologically, one has to consider that usually an anamnestic secondary immune response is characterized by high avidity and high affinity, besides being quantitatively relevant. Therefore, as a final result, exposure to SARS-CoV-2 by infection and/or vaccination can trigger immediate and violent cross-reactive attacks against the proteins that protect the human being from carcinogenesis.


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Conclusion

The findings described in [Tables 1] to [3] and [Supplementary Table S2] (available in online version only) indicate that molecular mimicry and cross-reactivity between peptides common to SARS-CoV-2 and tumor-related proteins might cause/contribute to cancer epidemics worldwide in the next future. The potential cancer risk might be enhanced by immunologic imprinting phenomena, given the fact that the comparative analyses shown in [Table 3] indicate the possibility that a preexisting immune response to previously encountered pathogens could be magnified and intensified following SARS-CoV-2 infection/active immunization. These data are disturbing and invite to immediately intensify clinical surveillance in oncology and to undertake rigid cancer prevention actions, including healthy lifestyle and continuous controls. It will be vital to formulate/implement actions that contemplate fast and safe procedures for clinical trials, development of specific and reliable tumor markers for diagnosis, accurate follow-up of treatments, and, administratively, medical health records, detailed registries, biobanks, health surveys, and coordinated observational studies. Never before do all the recommendations of the European plan for the fight against cancer appear current and necessary.[58] De facto, tumors appear to be the predominant pathologies that will populate the post pandemic long COVID-19.


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Conflict of Interest

None declared.

Supplementary Material


Address for correspondence

Darja Kanduc, PhD
Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari
Bari 70121
Italy   

Publication History

Received: 16 July 2021

Accepted: 02 August 2021

Publication Date:
07 September 2021 (online)

© 2021. 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/)

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