Genomic investigations of unexplained acute hepatitis in children.

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Morfopoulou, Sofia, Buddle, Sarah, Montaguth, Oscar Enrique Torres, Atkinson, Laura, Guerra-Assunção, José Afonso, Marjaneh, Mahdi Moradi, Chiozzi, Riccardo Zenezini, Storey, Nathaniel, Campos, Luis, Hutchinson, J Ciaran et al (show 80 more authors) , Counsell, John R, Pollara, Gabriele, Roy, Sunando, Venturini, Cristina, Antinao Diaz, Juan F, Siam, Ala'a, Tappouni, Luke J, Asgarian, Zeinab, Ng, Joanne, Hanlon, Killian S, Lennon, Alexander, McArdle, Andrew, Czap, Agata, Rosenheim, Joshua, Andrade, Catarina, Anderson, Glenn, Lee, Jack CD, Williams, Rachel, Williams, Charlotte A, Tutill, Helena, Bayzid, Nadua, Bernal, Luz Marina Martin, Macpherson, Hannah, Montgomery, Kylie-Ann, Moore, Catherine, Templeton, Kate, Neill, Claire, Holden, Matt, Gunson, Rory, Shepherd, Samantha J, Shah, Priyen, Cooray, Samantha, Voice, Marie, Steele, Michael, Fink, Colin, Whittaker, Thomas E, Santilli, Giorgia, Gissen, Paul, Kaufer, Benedikt B, Reich, Jana, Andreani, Julien, Simmonds, Peter, Alrabiah, Dimah K, Hereza, Sergi Castellano, Chikowore, Primrose, Odam, Miranda, Rampling, Tommy, Houlihan, Catherine, Hoschler, Katja, Talts, Tiina, Celma, Cristina, Gonzalez, Suam, Gallagher, Eileen, Simmons, Ruth, Watson, Conall, Mandal, Sema, Zambon, Maria, Chand, Meera, Hatcher, James, De, Surjo, Baillie, Kenneth, Semple, Malcolm Gracie ORCID: 0000-0001-9700-0418, DIAMONDS Consortium, , PERFORM Consortium, , ISARIC Consortium, , Martin, Joanne, Ushiro-Lumb, Ines, Noursadeghi, Mahdad, Deheragoda, Maesha, Hadzic, Nedim, Grammatikopoulos, Tassos, Brown, Rachel, Kelgeri, Chayarani, Thalassinos, Konstantinos, Waddington, Simon N, Jacques, Thomas S, Thomson, Emma, Levin, Michael, Brown, Julianne R and Breuer, Judith (2023) Genomic investigations of unexplained acute hepatitis in children. Nature, 617 (7961). pp. 564-573.

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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 UK ¹. 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.

Item Type:	Article
Uncontrolled Keywords:	DIAMONDS Consortium, ISARIC Consortium, PERFORM Consortium
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	28 Apr 2023 08:31
Last Modified:	30 Sep 2023 01:30
DOI:	10.1038/s41586-023-06003-w
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3169937