SARS-CoV-2-Induced Immunosuppression: A Molecular Mimicry Syndrome

Abstract

Background Contrary to immunological expectations, decay of adaptive responses against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) characterizes recovered patients compared with patients who had a severe disease course or died following SARS-CoV-2 infection. This raises the question of the causes of the virus-induced immune immunosuppression. Searching for molecular link(s) between SARS-CoV-2 immunization and the decay of the adaptive immune responses, SARS-CoV-2 proteome was analyzed for molecular mimicry with human proteins related to immunodeficiency. The aim was to verify the possibility of cross-reactions capable of destroying the adaptive immune response triggered by SARS-CoV-2.
Materials and Methods Human immunodeficiency-related proteins were collected from UniProt database and analyzed for sharing of minimal immune determinants with the SARS-CoV-2 proteome.
Results Molecular mimicry and consequent potential cross-reactivity exist between SARS-CoV-2 proteome and human immunoregulatory proteins such as nuclear factor kappa B (NFKB), and variable diversity joining V(D)J recombination-activating gene (RAG).
Conclusion The data (1) support molecular mimicry and the associated potential cross-reactivity as a mechanism that can underlie self-reactivity against proteins involved in B- and T-cells activation/development, and (2) suggest that the extent of the immunosuppression is dictated by the extent of the immune responses themselves. The higher the titer of the immune responses triggered by SARS-CoV-2 immunization, the more severe can be the cross-reactions against the human immunodeficiency-related proteins, the more severe the immunosuppression. Hence, SARS-CoV-2-induced immunosuppression can be defined as a molecular mimicry syndrome. Clinically, the data imply that booster doses of SARS-CoV-2 vaccines may have opposite results to those expected.

Keywords

SARS-CoV-2 / immunosuppression / molecular mimicry / cross-reactivity / NFKB / V(D)J RAG proteins

Funding

None.

Conflict of Interest

None declared.

References

[1] Lipsitch M, Krammer F, Regev-Yochay G, Lustig Y, Balicer RD.SARS-CoV-2 breakthrough infections in vaccinated individuals: measurement, causes and impact. Nat Rev Immunol 2022; 22(01): 57-65

[2] Jo DH, Minn D, Lim J.et al.Rapidly declining SARS-CoV-2 antibody titers within 4 months after BNT162b2 vaccination. Vaccines (Basel) 2021; 9(10): 1145

[3] Israel A, Merzon E, Schäffer AA.et al.Elapsed time since BNT162b2 vaccine and risk of SARS-CoV-2 infection: test negative design study. BMJ 2021; 375: e067873

[4] Israel A, Shenhar Y, Green I.et al.Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection. Vaccines (Basel) 2021; 10(01): 64

[5] Achiron A, Mandel M, Dreyer-Alster S, Harari G, Gurevich M.Humoral SARS-COV-2 IgG decay within 6 months in COVID-19 healthy vaccinees: The need for a booster vaccine dose?. Eur J Intern Med 2021; 94: 105-107

[6] Krutikov M, Palmer T, Tut G.et al.Prevalence and duration of detectable SARS-CoV-2 nucleocapsid antibodies in staff and residents of long-term care facilities over the first year of the pandemic (VIVALDI study): prospective cohort study in England. Lancet Healthy Longev 2022; 3(01): e13-e21

[7] Seow J, Graham C, Merrick B.et al.Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans. Nat Microbiol 2020; 5(12): 1598-1607

[8] Ibarrondo FJ, Fulcher JA, Goodman-Meza D.et al.Rapid decay of anti-SARS-CoV-2 antibodies in persons with mild COVID-19. N Engl J Med 2020; 383(11): 1085-1087

[9] Van Elslande J, Oyaert M, Ailliet S.et al.Longitudinal follow-up of IgG anti-nucleocapsid antibodies in SARS-CoV-2 infected patients up to eight months after infection. J Clin Virol 2021; 136: 104765

[10] Alfego D, Sullivan A, Poirier B, Williams J, Adcock D, Letovsky S.A population-based analysis of the longevity of SARS-CoV-2 antibody seropositivity in the United States. EClinicalMedicine 2021; 36: 100902

[11] Lee E, Oh JE.Humoral immunity against SARS-CoV-2 and the impact on COVID-19 pathogenesis. Mol Cells 2021; 44(06): 392-400

[12] Röltgen K, Powell AE, Wirz OF.et al. Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome. Sci Immunol2020; 5 (54): eabe0240

[13] Garcia-Beltran WF, Lam EC, Astudillo MG.et al. COVID-19-neutralizing antibodies predict disease severity and survival. Cell2021; 184 (02): 476-488.e11

[14] Hashem AM, Algaissi A, Almahboub SA.et al.Early humoral response correlates with disease severity and outcomes in COVID-19 patients. Viruses 2020; 12(12): 1390

[15] Wang Y, Zhang L, Sang L.et al.Kinetics of viral load and antibody response in relation to COVID-19 severity. J Clin Invest 2020; 130(10): 5235-5244

[16] Zhao J, Yuan Q, Wang H.et al.Antibody responses to SARS-CoV-2 in patients with novel coronavirus disease 2019. Clin Infect Dis 2020; 71(16): 2027-2034

[17] Van Elslande J, Gruwier L, Godderis L, Vermeersch P.Estimated half-life of SARS-CoV-2 anti-spike antibodies more than double the half-life of anti-nucleocapsid antibodies in healthcare workers. Clin Infect Dis 2021; 73(12): 2366-2368

[18] Chansaenroj J, Yorsaeng R, Posuwan N.et al.Long-term specific IgG response to SARS-CoV-2 nucleocapsid protein in recovered COVID-19 patients. Sci Rep 2021; 11(01): 23216

[19] Batra M, Tian R, Zhang C.et al.Role of IgG against N-protein of SARS-CoV2 in COVID19 clinical outcomes. Sci Rep 2021; 11(01): 3455

[20] Habel JR, Nguyen THO, van de Sandt CE. et al. Suboptimal SARS-CoV-2-specific CD8+ T cell response associated with the prominent HLA-A*02:01 phenotype. Proc Natl Acad Sci U S A 2020; 117(39): 24384-24391

[21] Yang J, Zhong M, Hong K.et al.Characteristics of T-cell responses in COVID-19 patients with prolonged SARS-CoV-2 positivity - a cohort study. Clin Transl Immunology 2021; 10(03): e1259

[22] Cohen CA, Li APY, Hachim A.et al.SARS-CoV-2 specific T cell responses are lower in children and increase with age and time after infection. Nat Commun 2021; 12(01): 4678

[23] Krüttgen A, Klingel H, Haase G, Haefner H, Imöhl M, Kleines M.Evaluation of the QuantiFERON SARS-CoV-2 interferon-γrelease assay in mRNA-1273 vaccinated health care workers. J Virol Methods 2021; 298: 114295

[24] Specter S, Bendinelli M, Friedman H. Virus-Induced Immunosuppression. New York, NY: Plenum Press; 1989: 1-477

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

[26] 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

[27] Kanduc D.Measles virus hemagglutinin epitopes are potential hotspots for crossreactions with immunodeficiency-related proteins. Future Microbiol 2015; 10(04): 503-515

[28] 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

[29] Zagury JF, Bernard J, Achour A.et al.Identification of CD4 and major histocompatibility complex functional peptide sites and their homology with oligopeptides from human immunodeficiency virus type 1 glycoprotein gp120: role in AIDS pathogenesis. Proc Natl Acad Sci U S A 1993; 90(16): 7573-7577

[30] Gulden PH, Fischer III P, Sherman NE.et al.A Listeria monocytogenes pentapeptide is presented to cytolytic T lymphocytes by the H2-M3 MHC class Ib molecule. Immunity 1996; 5(01): 73-79

[31] Malarkannan S, Gonzalez F, Nguyen V, Adair G, Shastri N.Alloreactive CD8+ T cells can recognize unusual, rare, and unique processed peptide/MHC complexes. J Immunol 1996; 157(10): 4464-4473

[32] Byers DE, Fischer Lindahl K.H2-M3 presents a nonformylated viral epitope to CTLs generated in vitro. J Immunol 1998; 161(01): 90-96

[33] Lockey TD, Surman S, Brown S.et al.A five-residue HIV envelope helper T cell determinant: does this peptide-MHC interaction leave the binding groove half empty?. AIDS Res Hum Retroviruses 2002; 18(15): 1141-1144

[34] Pieczenik G.Are the universes of antibodies and antigens symmetrical?. Reprod Biomed Online 2003; 6(02): 154-156

[35] Glithero A, Tormo J, Doering K, Kojima M, Jones EY, Elliott T.The crystal structure of H-2D(b) complexed with a partial peptide epitope suggests a major histocompatibility complex class I assembly intermediate. J Biol Chem 2006; 281(18): 12699-12704

[36] Kanduc D.Homology, similarity, and identity in peptide epitope immunodefinition. J Pept Sci 2012; 18(08): 487-494

[37] Raychaudhuri S, Sandor C, Stahl EA.et al.Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 2012; 44(03): 291-296

[38] 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

[39] Koch CP, Perna AM, Pillong M.et al.Scrutinizing MHC-I binding peptides and their limits of variation. PLOS Comput Biol 2013; 9(06): e1003088

[40] Kanduc D.Pentapeptides as minimal functional units in cell biology and immunology. Curr Protein Pept Sci 2013; 14(02): 111-120

[41] Morita D, Yamamoto Y, Suzuki J, Mori N, Igarashi T, Sugita M.Molecular requirements for T cell recognition of N-myristoylated peptides derived from the simian immunodeficiency virus Nef protein. J Virol 2013; 87(01): 482-488

[42] Hao SS, Zong MM, Zhang Z.et al.The inducing roles of the new isolated bursal hexapeptide and pentapeptide on the immune response of AIV vaccine in mice. Protein Pept Lett 2019; 26(07): 542-549

[43] Yamamoto Y, Morita D, Shima Y.et al.Identification and structure of an MHC Class I-encoded protein with the potential to present N-myristoylated 4-mer peptides to T cells. J Immunol 2019; 202(12): 3349-3358

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

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

[46] Asano T, Kaneko MK, Takei J, Tateyama N, Kato Y.Epitope mapping of the anti-CD44 monoclonal antibody (C44Mab-46) using the REMAP method. Monoclon Antib Immunodiagn Immunother 2021; 40(04): 156-161

[47] Hemed-Shaked M, Cowman MK, Kim JR.et al.MTADV 5-MER peptide suppresses chronic inflammations as well as autoimmune pathologies and unveils a new potential target-serum amyloid A. J Autoimmun 2021; 124: 102713

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

[49] 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

[50] Salimi N, Edwards L, Foos G.et al.A behind-the-scenes tour of the IEDB curation process: an optimized process empirically integrating automation and human curation efforts. Immunology 2020; 161(02): 139-147

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

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

[53] Pomerantz JL, Denny EM, Baltimore D.CARD11 mediates factor-specific activation of NF-kappaB by the T cell receptor complex. EMBO J 2002; 21(19): 5184-5194

[54] Hutcherson SM, Bedsaul JR, Pomerantz JL.Pathway-specific defects in T, B, and NK Cells and age-dependent development of high IgE in mice heterozygous for a CADINS-associated dominant negative CARD11 allele. J Immunol 2021; 207(04): 1150-1164

[55] Hara H, Wada T, Bakal C.et al.The MAGUK family protein CARD11 is essential for lymphocyte activation. Immunity 2003; 18(06): 763-775

[56] Jeelall YS, Wang JQ, Law HD.et al.Human lymphoma mutations reveal CARD11 as the switch between self-antigen-induced B cell death or proliferation and autoantibody production. J Exp Med 2012; 209(11): 1907-1917

[57] Stepensky P, Keller B, Buchta M.et al. Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects. J Allergy Clin Immunol2013; 131 (02): 477-85.e1

[58] Vale AM, Schroeder Jr HW.Clinical consequences of defects in B-cell development. J Allergy Clin Immunol 2010; 125(04): 778-787

[59] van Zelm MC, Reisli I, van der Burg M.et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med 2006; 354(18): 1901-1912

[60] Kuijpers TW, Bende RJ, Baars PA.et al.CD20 deficiency in humans results in impaired T cell-independent antibody responses. J Clin Invest 2010; 120(01): 214-222

[61] Abolhassani H.Specific immune response and cytokine production in CD70 deficiency. Front Pediatr 2021; 9: 615724

[62] Oettinger MA, Schatz DG, Gorka C, Baltimore D.RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 1990; 248(4962): 1517-1523

[63] Villa A, Sobacchi C, Notarangelo LD.et al.V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood 2001; 97(01): 81-88

[64] Gennery A.Recent advances in understanding RAG deficiencies. F1000 Res 2019; 8: F1000

[65] Dieli-Crimi R, Martínez-Gallo M, Franco-Jarava C.et al.Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations. Clin Immunol 2018; 195: 49-58

[66] Fliegauf M, Bryant VL, Frede N.et al.Haploinsufficiency of the NF-κB1 subunit p50 in common variable immunodeficiency. Am J Hum Genet 2015; 97(03): 389-403

[67] Chen K, Coonrod EM, Kumánovics A.et al.Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet 2013; 93(05): 812-824

[68] Franzoso G, Carlson L, Poljak L.et al.Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J Exp Med 1998; 187(02): 147-159

[69] Lo JC, Basak S, James ES.et al.Coordination between NF-kappaB family members p50 and p52 is essential for mediating LTbetaR signals in the development and organization of secondary lymphoid tissues. Blood 2006; 107(03): 1048-1055

[70] Ruddle NH, Akirav EM.Secondary lymphoid organs: responding to genetic and environmental cues in ontogeny and the immune response. J Immunol 2009; 183(04): 2205-2212

[71] Kuehn HS, Bernasconi A, Niemela JE.et al.A nonsense N-terminus NFKB2 mutation leading to haploinsufficiency in a patient with a predominantly antibody deficiency. J Clin Immunol 2020; 40(08): 1093-1101

[72] Kanduc D.Peptide cross-reactivity: the original sin of vaccines. Front Biosci (Schol Ed) 2012; 4(04): 1393-1401

RIGHTS & PERMISSIONS

Global Medical Genetics