Proteomic profiling reveals diagnostic signatures and pathogenic insights in multisystem inflammatory syndrome in children.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
05 Jun 2024
05 Jun 2024
Historique:
received:
12
11
2023
accepted:
22
05
2024
medline:
6
6
2024
pubmed:
6
6
2024
entrez:
5
6
2024
Statut:
epublish
Résumé
Multisystem inflammatory syndrome in children (MIS-C) is a severe disease that emerged during the COVID-19 pandemic. Although recognized as an immune-mediated condition, the pathogenesis remains unresolved. Furthermore, the absence of a diagnostic test can lead to delayed immunotherapy. Using state-of-the-art mass-spectrometry proteomics, assisted by artificial intelligence (AI), we aimed to identify a diagnostic signature for MIS-C and to gain insights into disease mechanisms. We identified a highly specific 4-protein diagnostic signature in children with MIS-C. Furthermore, we identified seven clusters that differed between MIS-C and controls, indicating an interplay between apolipoproteins, immune response proteins, coagulation factors, platelet function, and the complement cascade. These intricate protein patterns indicated MIS-C as an immunometabolic condition with global hypercoagulability. Our findings emphasize the potential of AI-assisted proteomics as a powerful and unbiased tool for assessing disease pathogenesis and suggesting avenues for future interventions and impact on pediatric disease trajectories through early diagnosis.
Identifiants
pubmed: 38839859
doi: 10.1038/s42003-024-06370-8
pii: 10.1038/s42003-024-06370-8
doi:
Substances chimiques
Biomarkers
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
688Subventions
Organisme : Uddannelses- og Forskningsministeriet (Ministry of Higher Education and Science)
ID : 0237-00004B
Organisme : Uddannelses- og Forskningsministeriet (Ministry of Higher Education and Science)
ID : 0237-00004B
Organisme : Uddannelses- og Forskningsministeriet (Ministry of Higher Education and Science)
ID : 0237-00004B
Organisme : Innovationsfonden (Innovation Fund Denmark)
ID : 0176-00020B
Organisme : Innovationsfonden (Innovation Fund Denmark)
ID : 0176-00020B
Organisme : Innovationsfonden (Innovation Fund Denmark)
ID : 0176-00020B
Organisme : Novo Nordisk Fonden (Novo Nordisk Foundation)
ID : NNF14C0001
Informations de copyright
© 2024. The Author(s).
Références
Feldstein et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N. Engl. J. Med. 383, 334–346 (2020).
doi: 10.1056/NEJMoa2021680
pubmed: 32598831
Dufort, E. M. et al. Multisystem inflammatory syndrome in children in New York state. N. Engl. J. Med. 383, 347–358 (2020).
doi: 10.1056/NEJMoa2021756
pubmed: 32598830
Consiglio, C. R. et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell 183, 968–981.e7 (2020).
doi: 10.1016/j.cell.2020.09.016
pubmed: 32966765
pmcid: 7474869
Burns, J. C. MIS-C: myths have been debunked, but mysteries remain. Nat. Rev. Rheumatol. 19, 70–71 (2023).
doi: 10.1038/s41584-022-00896-z
pubmed: 36609687
pmcid: 9817441
Holm, M. et al. Multisystem inflammatory syndrome in children occurred in one of four thousand children with severe acute respiratory syndrome coronavirus 2. Acta Paediatr. 110, 2581–2583 (2021).
doi: 10.1111/apa.15985
pubmed: 34129731
pmcid: 8444758
Nygaard, U. et al. Incidence and clinical phenotype of multisystem inflammatory syndrome in children after infection with the SARS-CoV-2 delta variant by vaccination status: a danish nationwide prospective cohort study. Lancet Child Adolesc. Health 6, 459–465 (2022).
doi: 10.1016/S2352-4642(22)00100-6
pubmed: 35526537
pmcid: 9072929
Bybeck Nielsen, A. et al. Clinical manifestations in children with staphylococcal bacteremia positive for panton-valentine leucocidin: a nationwide survey in a low methicillin-resistance setting. Pediatr. Infect. Dis. J. 39, e274–e276 (2020).
doi: 10.1097/INF.0000000000002722
pubmed: 32496412
Garcia-Beltran, W. F. et al. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 omicron variant. Cell 185, 457–466.e4 (2022).
doi: 10.1016/j.cell.2021.12.033
pubmed: 34995482
pmcid: 8733787
Levy, M. et al. Multisystem inflammatory syndrome in children by COVID-19 vaccination status of adolescents in France. JAMA 327, 281–283 (2022).
doi: 10.1001/jama.2021.23262
pubmed: 34928295
Holm, M. et al. Risk and phenotype of multisystem inflammatory syndrome in vaccinated and unvaccinated Danish children before and during the omicron wave. JAMA Pediatr. 176, 821–823 (2022).
doi: 10.1001/jamapediatrics.2022.2206
pubmed: 35675054
pmcid: 9178498
Noval Rivas, M., Porritt, R. A., Cheng, M. H., Bahar, I. & Arditi, M. COVID-19-associated multisystem inflammatory syndrome in children (MIS-C): a novel disease that mimics toxic shock syndrome-the superantigen hypothesis. J. Allergy Clin. Immunol. 147, 57–59 (2021).
doi: 10.1016/j.jaci.2020.10.008
pubmed: 33075409
Otar Yener, G. et al. Differences and similarities of multisystem inflammatory syndrome in children, Kawasaki disease and macrophage activating syndrome due to systemic juvenile idiopathic arthritis: a comparative study. Rheumatol. Int 42, 879–889 (2022).
doi: 10.1007/s00296-021-04980-7
pubmed: 34491393
McArdle, A. J. & Menikou, S. What is proteomics? Arch. Dis. Child Educ. Pr. Ed. 106, 178–181 (2021).
doi: 10.1136/archdischild-2019-317434
Aebersold, R. & Mann, M. Mass-spectrometric exploration of proteome structure and function. Nature 537, 347–355 (2016).
doi: 10.1038/nature19949
pubmed: 27629641
Geyer, P. E., Holdt, L. M., Teupser, D. & Mann, M. Revisiting biomarker discovery by plasma proteomics. Mol. Syst. Biol. 13, 942 (2017).
doi: 10.15252/msb.20156297
pubmed: 28951502
pmcid: 5615924
Yeoh, S. et al. Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children From Other Pediatric Infectious and Inflammatory Diseases. Pediatr Infect Dis J. 43, 444–453 (2024).
Jackson, H. R. et al. Diagnosis of multisystem inflammatory syndrome in children by a whole-blood transcriptional signature. J. Pediatr. Infect. Dis. Soc. 12, 322–331 (2023).
doi: 10.1093/jpids/piad035
Sacco, K. et al. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat. Med. 28, 1050–1062 (2022).
doi: 10.1038/s41591-022-01724-3
pubmed: 35177862
pmcid: 9119950
Ramaswamy, A. et al. Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children. Immunity 54, 1083–1095.e7 (2021).
doi: 10.1016/j.immuni.2021.04.003
pubmed: 33891889
pmcid: 8043654
Syrimi, E. et al. The immune landscape of SARS-CoV-2-associated multisystem inflammatory syndrome in children (MIS-C) from acute disease to recovery. iScience 24, 103215 (2021).
doi: 10.1016/j.isci.2021.103215
pubmed: 34632327
pmcid: 8487319
Porritt, R. A. et al. HLA class I-associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children. J. Clin. Invest 131, e146614 (2021).
doi: 10.1172/JCI146614
pubmed: 33705359
pmcid: 8121516
Mietus-Snyder, M. et al. Changes in HDL cholesterol, particles, and function associate with pediatric COVID-19 severity. Front Cardiovasc. Med. 9, 1033660 (2022).
doi: 10.3389/fcvm.2022.1033660
pubmed: 36312284
pmcid: 9597312
Verduci, E. et al. Blood fatty acids profile in MIS-C children. Metabolites 11, 721 (2021).
doi: 10.3390/metabo11110721
pubmed: 34822379
pmcid: 8624489
Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008).
doi: 10.1038/nature07201
pubmed: 18650913
Cioccari, L., Luethi, N. & Masoodi, M. Lipid mediators in critically Ill patients: a step towards precision medicine. Front Immunol. 11, 599853 (2020).
doi: 10.3389/fimmu.2020.599853
pubmed: 33324417
pmcid: 7724037
Pucino, V. & Guma, M. Editorial: The role of immunometabolism in autoimmune mediated and autoinflammatory disorders. Front Immunol. 13, 969939 (2022).
doi: 10.3389/fimmu.2022.969939
pubmed: 35911700
pmcid: 9336634
Kumar, R., Rivkin, M. J. & Raffini, L. Thrombotic complications in children with coronavirus disease 2019 and multisystem inflammatory syndrome of childhood. J. Thromb. Haemost. 21, 2313–2326 (2023).
doi: 10.1016/j.jtha.2023.05.020
pubmed: 37268064
Porritt, R.A. et al. The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children. J Clin Invest. 131, e151520 (2021).
Boucher, A. A. et al. Prolonged elevations of factor VIII and von willebrand factor antigen after multisystem inflammatory syndrome in children. J. Pediatr. Hematol. Oncol. 45, e427–e432 (2023).
doi: 10.1097/MPH.0000000000002583
pubmed: 36730963
Ankola, A. A. et al. Coagulation profiles and viscoelastic testing in multisystem inflammatory syndrome in children. Pediatr. Blood Cancer 68, e29355 (2021).
doi: 10.1002/pbc.29355
pubmed: 34532964
Geyer, P. E. et al. Plasma proteome profiling to assess human health and disease. Cell Syst. 2, 185–195 (2016).
doi: 10.1016/j.cels.2016.02.015
pubmed: 27135364
Barahona Afonso, A. F. & João, C. M. P. The production processes and biological effects of intravenous immunoglobulin. Biomolecules 6, 15 (2016).
doi: 10.3390/biom6010015
pubmed: 27005671
pmcid: 4808809
Santos, A. et al. A knowledge graph to interpret clinical proteomics data. Nat. Biotechnol. 40, 692–702 (2022).
doi: 10.1038/s41587-021-01145-6
pubmed: 35102292
pmcid: 9110295
Geyer, P. E. et al. Plasma proteome profiling to detect and avoid sample-related biases in biomarker studies. EMBO Mol. Med. 11, e10427 (2019).
doi: 10.15252/emmm.201910427
pubmed: 31566909
pmcid: 6835559
Shannon, P. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504 (2003).
doi: 10.1101/gr.1239303
pubmed: 14597658
pmcid: 403769
Pedregosa, F. et al. Scikit-learn: Machine Learning in Python. J. Mach. Learn. Res. 12, 2825–2830 (2011).
Diorio, C. et al. Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction. Nat. Commun. 12, 7222 (2021).
doi: 10.1038/s41467-021-27544-6
pubmed: 34893640
pmcid: 8664884
Perez-Riverol, Y. et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 50, D543–D552 (2022).
doi: 10.1093/nar/gkab1038
pubmed: 34723319