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Lookup NU author(s): Professor Marieke Emonts-le ClercqORCiD, Kathryn Bell, Professor John IsaacsORCiD, Dr Emma Lim, Owen Treloar
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023, The Author(s).Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.
Author(s): Morfopoulou S, Buddle S, Torres Montaguth OE, et al, Emonts M, Bell K, Isaacs JD, Lim EJ, Treloar O, DIAMONDS Consortium, PERFORM Consortium
Publication type: Article
Publication status: Published
Journal: Nature
Year: 2023
Volume: 617
Issue: 7961
Pages: 564-573
Print publication date: 18/05/2023
Online publication date: 30/03/2023
Acceptance date: 23/03/2023
Date deposited: 05/06/2023
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Nature Research
URL: https://doi.org/10.1038/s41586-023-06003-w
DOI: 10.1038/s41586-023-06003-w
Data Access Statement: The consensus genomes from viral WGS data are deposited in GenBank. IDs can be found in Supplementary Table 7 (HAdV), Supplementary Table 9 (AAV2) and Supplementary Table 10 (HHV6). The MS proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD035925. Code availability The code for metagenomics and PCR analysis can be found at https://github.com/sarah-buddle/unknown-hepatitis. The transcriptomics analysis code is available at https://github.com/innate2adaptive/Bulk-RNAseq-analysis/tree/main/Zscore_gene_expression_module_analysis. The proteomics differential expression analysis code can be found at https://github.com/MahdiMoradiMarjaneh/proteomics_and_transcriptomics_of_hepatitis.
PubMed id: 36996872
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