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DOI 10.1038/s41586-023-06003-w

Медицинская библиотека · Nature · 2023

Genomic investigations of unexplained acute hepatitis in children.

Morfopoulou Sofia, Buddle Sarah, Torres Montaguth Oscar Enrique, Atkinson Laura, Guerra-Assunção José Afonso, Moradi Marjaneh Mahdi, Zennezini Chiozzi Riccardo, Storey Nathaniel, Campos Luis, Hutchinson J Ciaran, 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 C D, Williams Rachel, Williams Charlotte A, Tutill Helena, Bayzid Nadua, Martin Bernal Luz Marina, 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, Castellano Sergi, 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, DIAMONDS Consortium, PERFORM Consortium, ISARIC 4C Investigators, 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, Breuer Judith

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Аннотация

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.

Для цитирования: Morfopoulou Sofia, Buddle Sarah, Torres Montaguth Oscar Enrique, Atkinson Laura, Guerra-Assunção José Afonso, Moradi Marjaneh Mahdi, Zennezini Chiozzi Riccardo, Storey Nathaniel, Campos Luis, Hutchinson J Ciaran, 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 C D, Williams Rachel, Williams Charlotte A, Tutill Helena, Bayzid Nadua, Martin Bernal Luz Marina, 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, Castellano Sergi, 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, DIAMONDS Consortium, PERFORM Consortium, ISARIC 4C Investigators, 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, Breuer Judith. Genomic investigations of unexplained acute hepatitis in children.. Nature. 2023. DOI: 10.1038/s41586-023-06003-w.

Предметные рубрики MeSH

Adenovirus Infections, HumanGene Expression ProfilingProteomicsB-LymphocytesLiverChildAcute DiseaseDependovirusHepatitisT-LymphocytesGenomicsHumansImmunohistochemistry
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