Exposure to SARS-CoV-2 and Infantile Diseases

Abstract

Background and Aim Immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in newborns and children after prophylactic immunization is currently a relevant research topic. The present study analyzes the issue by examining the possibility that the anti-SARS-CoV-2 immune responses are not uniquely directed against the virus but can—via molecular mimicry and the consequent cross-reactivity—also hit human proteins involved in infantile diseases.
Methods Human proteins that—if altered—associate with infantile disorders were searched for minimal immune pentapeptide determinants shared with SARS-CoV-2 spike glycoprotein (gp). Then, the shared pentapeptides were analyzed for immunologic potential and immunologic imprinting phenomena.
Results Comparative sequence analysis shows that: (1) numerous pentapeptides (namely, 54) are common to SARS-CoV-2 spike gp and human proteins that, when altered, are linked to infantile diseases; (2) all the shared peptides have an immunologic potential since they are present in experimentally validated SARS-CoV-2 spike gp-derived epitopes; and (3) many of the shared peptides are also hosted in infectious pathogens to which children can have already been exposed, thus making immunologic imprint phenomena feasible.
Conclusion Molecular mimicry and the consequent cross-reactivity can represent the mechanism that connects exposure to SARS-CoV-2 and various pediatric diseases, with a fundamental role of the immunologic memory and the history of the child's infections in determining and specifying the immune response and the pathologic autoimmune sequela.

Keywords

SARS-CoV-2 spike gp / molecular mimicry / peptide sharing / cross-reactivity / immunologic imprinting / autoimmune / infantile diseases

References

[1] Kapustova L, Petrovicova O, Banovcin P.et al.COVID-19 and the differences in physiological background between children and adults and their clinical consequences. Physiol Res 2021; 70(S2): S209-S225

[2] Ludvigsson JF.Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr 2020; 109(06) 1088-1095

[3] Islam MS, Larpruenrudee P, Saha SC.et al.How severe acute respiratory syndrome coronavirus-2 aerosol propagates through the age-specific upper airways. Phys Fluids 2021; 33(08) 081911

[4] Ladani AP, Loganathan M, Kolikonda MK, Lippmann S.COVID-19 Legacy. South Med J 2021; 114(12) 751-759

[5] Ergenc Z, Kepenekli E, Çetin E.et al.Incidence of multisystem inflammatory syndrome in children and the comorbidity scores in pediatric coronavirus disease 2019 cases. Pediatr Int (Roma) 2022; 64(01) e15084

[6] Payne AB, Gilani Z, Godfred-Cato S.et al; MIS-C Incidence Authorship Group. Incidence of multisystem inflammatory syndrome in children among US persons infected with SARS-CoV-2. JAMA Netw Open 2021; 4(06) e2116420

[7] Chen Y, Xu Z, Wang P.et al.New-onset autoimmune phenomena post-COVID-19 vaccination. Immunology 2022; 165(04) 386-401

[8] Churilov LP, Kanduc D, Ryabkova VA.COVID-19: adrenal response and molecular mimicry. Isr Med Assoc J 2021; 23(10) 618-619

[9] Kanduc D.From anti-SARS-CoV-2 immune responses to COVID-19 via molecular mimicry. Antibodies (Basel) 2020; 9(03) 33

[10] Kanduc D.From anti-SARS-CoV-2 immune response to the cytokine storm via molecular mimicry. Antibodies (Basel) 2021; 10(04) 36

[11] 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

[12] Garg RK, Paliwal VK.Spectrum of neurological complications following COVID-19 vaccination. Neurol Sci 2022; 43(01) 3-40

[13] Gambichler T, Boms S, Susok L.et al.Cutaneous findings following COVID-19 vaccination: review of world literature and own experience. J Eur Acad Dermatol Venereol 2022; 36(02) 172-180

[14] Mehta SK, Sunder A.Getting paralysed after COVID: Guillain-Barre syndrome. J Family Med Prim Care 2021; 10(07) 2706-2708

[15] Moody R, Wilson K, Flanagan KL, Jaworowski A, Plebanski M.Adaptive immunity and the risk of autoreactivity in COVID-19. Int J Mol Sci 2021; 22(16) 8965

[16] Chittal A, Rao S, Lakra P, Nacu N, Haas C.A case of COVID-19 vaccine-induced thrombotic thrombocytopenia. J Community Hosp Intern Med Perspect 2021; 11(06) 776-778

[17] Shi H, Zuo Y, Navaz S.et al.Endothelial cell-activating antibodies in COVID-19. Arthritis Rheumatol 2022; 74(07) 1132-1138

[18] Kanduc D.Hydrophobicity and the physico-chemical basis of immunotolerance. Pathobiology 2020; 87(04) 268-276

[19] Kanduc D.The role of proteomics in defining autoimmunity. Expert Rev Proteomics 2021; 18(03) 177-184

[20] UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res 2019; 47(D1): D506-D515

[21] Vita R, Mahajan S, Overton JA.et al.The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Res 2019; 47(D1): D339-D343

[22] Hanks S, Adams S, Douglas J.et al.Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis. Am J Hum Genet 2003; 73(04) 791-800

[23] Kato M, Das S, Petras K.et al.Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat 2004; 23(02) 147-159

[24] Swoboda KJ, Kanavakis E, Xaidara A.et al.Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Ann Neurol 2004; 55(06) 884-887

[25] Deprez L, Weckhuysen S, Peeters K.et al.Epilepsy as part of the phenotype associated with ATP1A2 mutations. Epilepsia 2008; 49(03) 500-508

[26] Gao H, Boustany RM, Espinola JA.et al.Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am J Hum Genet 2002; 70(02) 324-335

[27] Cabral WA, Makareeva E, Colige A.et al.Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing. J Biol Chem 2005; 280(19) 19259-19269

[28] Alfadhel M, Lillquist YP, Waters PJ.et al.Infantile cardioencephalopathy due to a COX15 gene defect: report and review. Am J Med Genet A 2011; 155A(04) 840-844

[29] Attard M, Jean G, Forestier L.et al.Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin. Hum Mol Genet 1999; 8(13) 2507-2514

[30] Uusimaa J, Hinttala R, Rantala H.et al.Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus. Epilepsia 2008; 49(06) 1038-1045

[31] Bai D, Shi W, Qi Z.et al.Clinical feature and waveform in infantile nystagmus syndrome in children with FRMD7 gene mutations. Sci China Life Sci 2017; 60(07) 707-713

[32] Rumping L, Büttner B, Maier O.et al.Identification of a loss-of-function mutation in the context of glutaminase deficiency and neonatal epileptic encephalopathy. JAMA Neurol 2019; 76(03) 342-350

[33] Nava C, Dalle C, Rastetter A.et al; EuroEPINOMICS RES Consortium. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet 2014; 46(06) 640-645

[34] Gaignard P, Gonzales E, Ackermann O.et al.Mitochondrial infantile liver disease due to TRMU gene mutations: three new cases. JIMD Rep 2013; 11: 117-123

[35] Al-Sayed MD, Al-Zaidan H, Albakheet A.et al.Mutations in NALCN cause an autosomal-recessive syndrome with severe hypotonia, speech impairment, and cognitive delay. Am J Hum Genet 2013; 93(04) 721-726

[36] Maksimova N, Hara K, Nikolaeva I.et al.Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly. J Med Genet 2010; 47(08) 538-548

[37] Bonten E, van der Spoel A, Fornerod M, Grosveld G, d'Azzo A. Characterization of human lysosomal neuraminidase defines the molecular basis of the metabolic storage disorder sialidosis. Genes Dev 1996; 10(24) 3156-3169

[38] Blom TS, Linder MD, Snow K.et al.Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease. Hum Mol Genet 2003; 12(03) 257-272

[39] Magen D, Berger L, Coady MJ.et al.A loss-of-function mutation in NaPi-IIa and renal Fanconi's syndrome. N Engl J Med 2010; 362(12) 1102-1109

[40] Basel-Vanagaite L, Muncher L, Straussberg R.et al.Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis. Ann Neurol 2006; 60(02) 214-222

[41] Spiegel R, Saada A, Flannery PJ.et al.Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation. J Med Genet 2016; 53(02) 127-131

[42] Depienne C, Bouteiller D, Keren B.et al.Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet 2009; 5(02) e1000381

[43] Yik WY, Steinberg SJ, Moser AB, Moser HW, Hacia JG.Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders. Hum Mutat 2009; 30(03) E467-E480

[44] Johnstone DL, Nguyen TT, Murakami Y.et al; Care4Rare Canada Consortium. Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy. Hum Mol Genet 2017; 26(09) 1706-1715

[45] Li M, Niu F, Zhu X.et al.PRRT2 mutant leads to dysfunction of glutamate signaling. Int J Mol Sci 2015; 16(05) 9134-9151

[46] Hu H, Matter ML, Issa-Jahns L.et al.Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness. Ann Clin Transl Neurol 2014; 1(12) 1024-1035

[47] Garcia-Diaz B, Barros MH, Sanna-Cherchi S.et al.Infantile encephaloneuromyopathy and defective mitochondrial translation are due to a homozygous RMND1 mutation. Am J Hum Genet 2012; 91(04) 729-736

[48] Haijes HA, Koster MJE, Rehmann H.et al.De novo heterozygous POLR2A variants cause a neurodevelopmental syndrome with profound infantile-onset hypotonia. Am J Hum Genet 2019; 105(02) 283-301

[49] Kurian MA, Zhen J, Cheng SY.et al.Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia. J Clin Invest 2009; 119(06) 1595-1603

[50] Harkin LA, McMahon JM, Iona X.et al; Infantile Epileptic Encephalopathy Referral Consortium. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 2007; 130(Pt 3): 843-852

[51] Heron SE, Crossland KM, Andermann E.et al.Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet 2002; 360(9336): 851-852

[52] Vanoye CG, Gurnett CA, Holland KD, George Jr AL, Kearney JA.Novel SCN3A variants associated with focal epilepsy in children. Neurobiol Dis 2014; 62: 313-322

[53] Trudeau MM, Dalton JC, Day JW, Ranum LP, Meisler MH.Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. J Med Genet 2006; 43(06) 527-530

[54] Hu H, Eggers K, Chen W.et al.ST3GAL3 mutations impair the development of higher cognitive functions. Am J Hum Genet 2011; 89(03) 407-414

[55] Simpson MA, Cross H, Proukakis C.et al.Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet 2004; 36(11) 1225-1229

[56] Nikali K, Saharinen J, Peltonen L. cDNA cloning, expression profile and genomic structure of a novel human transcript on chromosome 10q24, and its analyses as a candidate gene for infantile onset spinocerebellar ataxia. Gene 2002; 299(1-2): 111-115

[57] Jacob FD, Ho ES, Martinez-Ojeda M, Darras BT, Khwaja OS.Case of infantile onset spinocerebellar ataxia type 5. J Child Neurol 2013; 28(10) 1292-1295

[58] Saitsu H, Kato M, Mizuguchi T.et al.De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet 2008; 40(06) 782-788

[59] Ostergaard E, Christensen E, Kristensen E.et al.Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion. Am J Hum Genet 2007; 81(02) 383-387

[60] Casey JP, McGettigan P, Lynam-Lennon N. et al. Identification of a mutation in LARS as a novel cause of infantile hepatopathy. Mol Genet Metab 2012; 106(03) 351-358

[61] Basel-Vanagaite L, Hershkovitz T, Heyman E.et al.Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. Am J Hum Genet 2013; 93(03) 524-529

[62] Sun Y, Almomani R, Breedveld GJ.et al.Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease). Hum Mutat 2013; 34(05) 706-713

[63] Kanduc D.The comparative biochemistry of viruses and humans: an evolutionary path towards autoimmunity. Biol Chem 2019; 400(05) 629-638

[64] Choudhry H, Bakhrebah MA, Abdulaal WH.et al.Middle East respiratory syndrome: pathogenesis and therapeutic developments. Future Virol 2019; 14(04) 237-246

[65] Su S, Wong G, Shi W.et al.Epidemiology, genetic recombination, and pathogenesis of Coronaviruses. Trends Microbiol 2016; 24(06) 490-502

[66] Francis T, Salk JE, Quilligan JJ.Experience with vaccination against influenza in the spring of 1947: a preliminary report. Am J Public Health Nations Health 1947; 37(08) 1013-1016

[67] Lucchese G, Kanduc D. The Guillain-Barrè peptide signatures: from Zika virus to Campylobacter, and beyond. Virus Adapt Treat 2017; 9: 1-11

[68] Lucchese G, Kanduc D.Minimal immune determinants connect Zika virus, human cytomegalovirus, and Toxoplasma gondii to microcephaly-related human proteins. Am J Reprod Immunol 2017; 77(02) e12608

[69] Kanduc D. Anti-SARS-CoV-2 immune response and sudden death: Titin as a link. Adv Stud Biol 2021; 13: 37-44

[70] 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

[71] Davenport FM, Hennessy AV, Francis Jr T.Epidemiologic and immunologic significance of age distribution of antibody to antigenic variants of influenza virus. J Exp Med 1953; 98(06) 641-656

[72] Fevang B, Wyller VBB, Mollnes TE.et al.Lasting immunological imprint of primary Epstein-Barr virus infection with associations to chronic low-grade inflammation and fatigue. Front Immunol 2021; 12: 715102

RIGHTS & PERMISSIONS

2023 Global Medical Genetics