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Genomic investigations of unexplained acute hepatitis in children

Lookup NU author(s): Professor Marieke Emonts-le ClercqORCiD, Kathryn Bell, Professor John IsaacsORCiD, Dr Emma Lim, Owen Treloar

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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

PubMed id: 36996872


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Funding

Funder referenceFunder name
848196
203268/Z/16/Z
207511/Z/17/Z
668303
Cancer Research UK
Brain Tumour Charity
Children with Cancer UK
CO-CIN-01
CV220-169
Department of Health and Social Care
European Union
GOSH Children’s Charity
MC_PC_19059
National Institute for Health and Care Research
National Institute for Health Research (NIHR)
NIHR Blood and Transplant Research Unit in Genomics to Enhance Microbiology Screening (GEMS)
NIHR University College London Hospitals Biomedical Research Centre
NIHR203338
Olivia Hodson Cancer Fund
NIHR GOSH Biomedical Research Centre
UKHSA
UKRI
Wellcome Trust

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