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 Zennezini 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. Hanlon, Alexander Lennon, Andrew McArdle, Agata Czap, Joshua Rosenheim, Catarina Andrade, Glenn Anderson, Jack C. D. Lee, Rachel Williams, Charlotte A. Williams, Helena J. Tutill, Nadua Bayzid, Luz Marina Martin Bernal, Hannah Macpherson, Kylie-Ann Montgomery, Catherine Moore, Kate Templeton, Claire Neill, Matthew T. G. Holden, Rory Gunson, Samantha J. Shepherd, Priyen Shah, Samantha Cooray, Marie Voice, M.A. Steele, Colin G. Fink, Thomas E. Whittaker, Giorgia Santilli, Paul Gissen, Benedikt B. Kaufer, Jana Reich, Julien Andréani, Peter Simmonds, Dimah K. Alrabiah, Sergi Castellano, Primrose Chikowore, Miranda Odam, Tommy Rampling, Catherine Houlihan, Katja Höschler, Tiina Talts, Cristina Celma, Suam Gonzalez, Eileen Gallagher, Ruth Simmons, Conall Watson, Sema Mandal, Maria Zambon, Meera Chand, James Hatcher, Surjo De, J. Kenneth Baillie, Malcolm G. Semple, Evangelos Bellos, Claire Broderick, Samuel Channon‐Wells, Tisham De, Giselle D’Souza, Leire Estramiana Elorrieta, Diego Estrada‐Rivadeneyra, Rachel Galassini, Dominic Habgood-Coote, Shea Hamilton, Heather Jackson, James Kavanagh, Mahdi Moradi Marjaneh, Stephanie Menikou, Samuel Nichols, Ruud Nijman, Harsita Patel, Ivana Pennisi, Oliver Powell, Ruth Reid, Ortensia Vito, Elizabeth Whittaker, Clare Wilson, Rebecca Womersley, Amina Abdulla, Sarah Darnell, Sobia Mustafa, Pantelis Georgiou
Abstract
. 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.