{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T23:25:23Z","timestamp":1772148323915,"version":"3.50.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The contribution of antibody-mediated responses to COVID\u00a0-\u00a019 outcomes remains unclear, particularly regarding cross-reactivity with unrelated pathogens. While co-infections are known to influence disease progression, the broader landscape of IgG reactivity during SARS-CoV-2 infection has not been systematically explored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We employed a high-density peptide microarray containing 4,344 linear epitopes from 37 viruses, 27 bacteria, 17 parasites, and 8 fungi to characterize serum IgG repertoires from individuals with moderate (n = 39) or severe (n = 40) COVID\u00a0-\u00a019. Controls included pre-pandemic healthy donors and a pooled intravenous immunoglobulin (IVIg) formulation. Data analysis included intensity ranking, epitope mapping, and comparative analysis of mean signal intensities for each epitope between the COVID-Mod and COVID-Sev groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>COVID\u00a0-\u00a019 patients showed widespread IgG reactivity against diverse pathogens, with patterns differing by disease severity. Severe cases displayed broader and more intense reactivity, notably against hepatitis C virus (HCV), SARS-CoV-1, influenza A, Mycobacterium tuberculosis, and Plasmodium falciparum. Moderate cases showed preferential recognition of epitopes from HTLV-I, Neisseria meningitidis, and Trypanosoma cruzi. These findings suggest that SARS-CoV-2 infection modulates pre-existing humoral memory, possibly through epitope spreading or immune reprogramming.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>SARS-CoV-2 infection reshapes the IgG epitope repertoire in a severity-dependent manner, extending to antigens from unrelated pathogens. This phenomenon may reflect underlying immune dysregulation or idiotype-driven interactions. Comprehensive profiling of pathogen-related IgG responses may reveal potential biomarkers of disease severity. This phenomenon may inform future investigations aimed at improving personalized management strategies for co-infected or immunocompromised patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1668223","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T05:38:25Z","timestamp":1756877905000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Severity-dependent IgG epitope profiling in COVID-19 reveals differential recognition of pathogen-derived antigens"],"prefix":"10.3389","volume":"16","author":[{"given":"Lais Alves","family":"do Nascimento","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"NicolleRakanidis","family":"Machado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jo\u00e3o Vitor da Silva","family":"Borges","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz Oliveira","family":"Fagundes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabella Siuffi","family":"Bergamasco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio da Ressurei\u00e7\u00e3o","family":"Sgnotto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9 Luis Lacerda","family":"Bachi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Notomi","family":"Sato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jefferson Russo","family":"Victor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2012-7","article-title":"A pneumonia outbreak associated with a new coronavirus of probable bat origin","volume":"579","author":"Zhou","year":"2020","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms11041048","article-title":"Special issue: advances in SARS-coV-2 infection","volume":"11","author":"Contini","year":"2023","journal-title":"Microorganisms"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2024.1334152","article-title":"SARS-CoV-2: pathogenesis, therapeutics, variants, and vaccines","volume":"15","author":"Li","year":"2024","journal-title":"Front Microbiol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25158155","article-title":"Comprehensive review of COVID-19: epidemiology, pathogenesis, advancement in diagnostic and detection techniques, and post-pandemic treatment strategies","volume":"25","author":"Chung","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms10061193","article-title":"Advanced molecular and immunological diagnostic methods to detect SARS-coV-2 infection","volume":"10","author":"Rotondo","year":"2022","journal-title":"Microorganisms"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2020.05.046","article-title":"Co-infections in people with COVID-19: a systematic review and meta-analysis","volume":"81","author":"Lansbury","year":"2020","journal-title":"J Infect"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0012136","article-title":"Systematic review and meta-analysis of Tuberculosis and COVID-19 Co-infection: Prevalence, fatality, and treatment considerations","volume":"18","author":"Wang","year":"2024","journal-title":"PloS Negl Trop Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.2365","article-title":"Respiratory viral co-infections in patients with COVID-19 and associated outcomes: A systematic review and meta-analysis","volume":"33","author":"Krumbein","year":"2023","journal-title":"Rev Med Virol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1186\/s12879-023-08117-y","article-title":"Viral reactivations and co-infections in COVID-19 patients: a systematic review","volume":"23","author":"Kim","year":"2023","journal-title":"BMC Infect Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1428645","article-title":"Autoantibodies in COVID-19 survivors with post-COVID symptoms: a systematic review","volume":"15","author":"Notarte","year":"2024","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4081\/aiua.2021.1.115","article-title":"COVID-19 and male fertility: Taking stock of one year after the outbreak began","volume":"93","author":"Delle Fave","year":"2021","journal-title":"Arch Ital Urol Androl"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtauto.2023.100222","article-title":"Impact of the COVID-19 pandemic on temporal trends of biological indicators of autoimmunity","volume":"7","author":"Van Regemorter","year":"2023","journal-title":"J Transl Autoimmun"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06651-y","article-title":"Distinguishing features of long COVID identified through immune profiling","volume":"623","author":"Klein","year":"2023","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03631-y","article-title":"Diverse functional autoantibodies in patients with COVID-19","volume":"595","author":"Wang","year":"2021","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13919","article-title":"Deciphering the igG idiotype network through proteomic analysis of potential targets in SARS-coV-2-induced immune responses","volume":"175","author":"MaChado","year":"2025","journal-title":"Immunology"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02084-1","article-title":"Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis","volume":"28","author":"Achleitner","year":"2023","journal-title":"Mol Psychiatry"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12335","article-title":"Do different IgG repertoires play a role in B- and T-cell functional modulation during ontogeny? The \"hooks without bait\" theory","volume":"98","author":"Victor","year":"2020","journal-title":"Immunol Cell Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2016.1244592","article-title":"Allergen-specific IgG as a mediator of allergy inhibition: Lessons from mother to child","volume":"13","author":"Victor","year":"2017","journal-title":"Hum Vaccines Immunotherapeutics"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/780386","article-title":"Influence of maternal immunization with allergens on the thymic maturation of lymphocytes with regulatory potential in children: a broad field for further exploration","volume":"2014","author":"Victor","year":"2014","journal-title":"J Immunol Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s12874-023-02139-5","article-title":"Estimating cutoff values for diagnostic tests to achieve target specificity using extreme value theory","volume":"24","author":"Pugh","year":"2024","journal-title":"BMC Med Res Methodol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00809-x","article-title":"The impact of pre-existing cross-reactive immunity on SARS-CoV-2 infection and vaccine responses","volume":"23","author":"Murray","year":"2023","journal-title":"Nat Rev Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"6496","DOI":"10.1038\/s41598-022-10230-y","article-title":"Cross-reactive antibodies elicited to conserved epitopes on SARS-CoV-2 spike protein after infection and vaccination","volume":"12","author":"Geanes","year":"2022","journal-title":"Sci Rep"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd4250","article-title":"Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity","volume":"370","author":"Shrock","year":"2020","journal-title":"Science"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/sji.13344","article-title":"Unveiling the intricacies of COVID-19: Autoimmunity, multi-organ manifestations and the role of autoantibodies","volume":"99","author":"Ding","year":"2024","journal-title":"Scand J Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.821595","article-title":"Heterologous immunity between SARS-coV-2 and pathogenic bacteria","volume":"13","author":"Eggenhuizen","year":"2022","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03207-w","article-title":"Evolution of antibody immunity to SARS-CoV-2","volume":"591","author":"Gaebler","year":"2021","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00814-z","article-title":"Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19","volume":"21","author":"Woodruff","year":"2020","journal-title":"Nat Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abd3876","article-title":"Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19","volume":"12","author":"Zuo","year":"2020","journal-title":"Sci Transl Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102597","article-title":"Covid-19 and autoimmunity","volume":"19","author":"Ehrenfeld","year":"2020","journal-title":"Autoimmun Rev"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-00789-5","article-title":"Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies","volume":"5","author":"Lee","year":"2020","journal-title":"Nat Microbiol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2024.03.014","article-title":"IgG from individuals without atopy arising as mediators of a nonatopic profile in human peripheral CD4+ T cells","volume":"132","author":"Cunha","year":"2024","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"7274","DOI":"10.1038\/s41598-024-57950-x","article-title":"IgG from Dermatophagoides pteronyssinus (Der p)-atopic individuals modulates non-atopic thymic B cell phenotype (alfa-4\/beta-7) and cytokine production (IFN-\u03b3, IL-9, and IL-10) with direct membrane interaction","volume":"14","author":"de-Apoena Reche","year":"2024","journal-title":"Sci Rep"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/falgy.2021.650235","article-title":"Non-atopic neonatal thymic innate lymphoid cell subsets (ILC1, ILC2, and ILC3) identification and the modulatory effect of igG from dermatophagoides pteronyssinus (Derp)-atopic individuals","volume":"28","author":"Sousa","year":"2021","journal-title":"Front Allergy"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.23822\/EurAnnACI.1764-1489.157","article-title":"IgG from atopic individuals can mediate non-atopic infant thymic and adult peripheral CD8","volume":"53","author":"Rodrigues de Sousa","year":"2021","journal-title":"Eur Ann Allergy Clin Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/cells9102239","article-title":"The potential of igG to induce murine and human thymic maturation of IL-10+ B cells (B10) revealed in a pilot study","volume":"9","author":"Inoue","year":"2020","journal-title":"Cells"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s00005-019-00545-6","article-title":"IgG from non-atopic individuals induces in vitro IFN-\u03b3 and IL-10 production by human intra-thymic \u03b3\u03b4T cells: A comparison with atopic igG and IVIg","volume":"67","author":"Santos","year":"2019","journal-title":"Arch Immunol Ther Exp (Warsz)"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23126872","article-title":"IgG from adult atopic dermatitis (AD) patients induces nonatopic neonatal thymic gamma-delta T cells (\u03b3\u03b4T) to acquire IL-22\/IL-17 secretion profile with skin-homing properties and epigenetic implications mediated by miRNA","volume":"23","author":"Fagundes","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23126867","article-title":"IgG from adult atopic dermatitis (AD) patients induces thymic IL-22 production and CLA expression on CD4+ T cells: possible epigenetic implications mediated by miRNA","volume":"23","author":"de Sousa","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/ijd.14688","article-title":"IgG from atopic dermatitis patients induces non-atopic infant thymic invariant natural killer T (iNKT) cells to produce IL-4, IL-17, and IL-10","volume":"59","author":"Santos","year":"2019","journal-title":"Int J Dermatol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/ijd.13907","article-title":"IgG from atopic dermatitis patients induces IL-17 and IL-10 production in infant intrathymic TCD4 and TCD8 cells","volume":"57","author":"Sgnotto","year":"2018","journal-title":"Int J Dermatol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2023.1239706","article-title":"Differential modulation of IL-4, IL-10, IL-17, and IFN-\u03b3 production mediated by IgG from Human T-lymphotropic virus-1 (HTLV-1) infected patients on healthy peripheral T (CD4+, CD8+, and \u03b3\u03b4) and B cells","volume":"10","author":"MaChado","year":"2023","journal-title":"Front Med"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0000000000002182","article-title":"IgG from HIV-1-exposed seronegative and HIV-1-infected subjects differently modulates IFN-\u03b3 Production by thymic T and B cells","volume":"82","author":"da Ressurei\u00e7\u00e3o Sgnotto","year":"2019","journal-title":"J Acquir Immune Defic Syndr"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1159\/000431173","article-title":"Effects of intramuscular injection of autologous immunoglobulin on clinical severity and serum igE concentration in patients with atopic dermatitis","volume":"231","author":"Nahm","year":"2015","journal-title":"Dermatology"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4168\/aair.2016.8.4.375","article-title":"Autologous immunoglobulin therapy in patients with severe recalcitrant atopic dermatitis: long-term changes of clinical severity and laboratory parameters","volume":"8","author":"Nahm","year":"2016","journal-title":"Allergy Asthma Immunol Res"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.intimp.2017.08.020","article-title":"Immunomodulatory effects induced by intramuscular administration of autologous total immunoglobulin G in patients with atopic dermatitis","volume":"52","author":"Cho","year":"2017","journal-title":"Int Immunopharmacol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4168\/aair.2020.12.6.949","article-title":"Efficacy, safety, and immunomodulatory effect of the intramuscular administration of autologous total immunoglobulin G for atopic dermatitis: A randomized clinical trial","volume":"12","author":"Nahm","year":"2020","journal-title":"Allergy Asthma Immunol Res"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3349\/ymj.2022.0559","article-title":"Intramuscular injection of autologous serum in adolescent and adult patients with atopic dermatitis: A preliminary randomized clinical trial","volume":"64","author":"Nahm","year":"2023","journal-title":"Yonsei Med J"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines13070694","article-title":"Proteomic profiling of human peripheral blood cell targets of igG induced by SARS-coV-2: insights into vaccine safety","volume":"13","author":"MaChado","year":"2025","journal-title":"Vaccines (Basel)"},{"key":"B49","doi-asserted-by":"publisher","first-page":"95","DOI":"10.3892\/br.2023.1677","article-title":"IgG from patients with mild or severe COVID\u221219 reduces the frequency and modulates the function of peripheral mucosal-associated invariant T cells in PBMCs from healthy individuals","volume":"19","author":"Rakanidis MaChado","year":"2023","journal-title":"BioMed Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1668223\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T05:38:26Z","timestamp":1756877906000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1668223\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,3]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2025.1668223"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1668223","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,3]]},"article-number":"1668223"}}