Genomic investigations of unexplained acute hepatitis in children

Sofia Morfopoulou, Sarah Buddle, Oscar Enrique Torres Montaguth, Laura Atkinson, José Afonso Guerra-Assunção, Mahdi Moradi Marjaneh, Riccardo Zenezini Chiozzi, Nathaniel Storey, Luis Campos, J. Ciaran Hutchinson, John R. Counsell, Gabriele Pollara, Sunando Roy, Cristina Venturini, Juan F. Antinao Diaz, Ala’a Siam, Luke J. Tappouni, Zeinab Asgarian, Joanne Ng, Killian S. HanlonAlexander Lennon, Andrew McArdle, Agata Czap, Joshua Rosenheim, Catarina Andrade, Glenn Anderson, Jack C. D. Lee, Rachel Williams, Charlotte A. Williams, Helena Tutill, Nadua Bayzid, Luz Marina Martin Bernal, Hannah Macpherson, Kylie-Ann Montgomery, Catherine Moore, Kate Templeton, Claire Neill, Matt Holden, Rory Gunson, Samantha J. Shepherd, Priyen Shah, Samantha Cooray, Marie Voice, Michael Steele, Colin Fink, Thomas E. Whittaker, Giorgia Santilli, Paul Gissen, Benedikt B. Kaufer, Jana Reich, DIAMONDS consortium, ISARIC 4C Investigators, PERFORM Consortium, Judith Breuer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)
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Abstract

Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded 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 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.

Original languageEnglish
Pages (from-to)564-592
Number of pages29
JournalNature
Volume617
Early online date30 Mar 2023
DOIs
Publication statusPublished - 18 May 2023

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