TY - JOUR
T1 - Genomic investigations of unexplained acute hepatitis in children
AU - Morfopoulou, Sofia
AU - Buddle, Sarah
AU - Torres Montaguth, Oscar Enrique
AU - Atkinson, Laura
AU - Guerra-Assunção, José Afonso
AU - Moradi Marjaneh, Mahdi
AU - Zennezini Chiozzi, Riccardo
AU - Storey, Nathaniel
AU - Campos, Luis
AU - Hutchinson, J. Ciaran
AU - Counsell, John R.
AU - Pollara, Gabriele
AU - Roy, Sunando
AU - Venturini, Cristina
AU - Antinao Diaz, Juan F.
AU - Siam, Ala’a
AU - Tappouni, Luke J.
AU - Asgarian, Zeinab
AU - Ng, Joanne
AU - Hanlon, Killian S.
AU - Lennon, Alexander
AU - McArdle, Andrew
AU - Czap, Agata
AU - Rosenheim, Joshua
AU - Andrade, Catarina
AU - Anderson, Glenn
AU - Lee, Jack C.D.
AU - Williams, Rachel
AU - Williams, Charlotte A.
AU - Tutill, Helena
AU - Bayzid, Nadua
AU - Martin Bernal, Luz Marina
AU - Macpherson, Hannah
AU - Montgomery, Kylie Ann
AU - Moore, Catherine
AU - Templeton, Kate
AU - Neill, Claire
AU - Holden, Matt
AU - Breuer, Judith
AU - DIAMONDS Consortium
AU - PERFORM consortium
AU - Grāvele, Dagne
AU - Deksne, Dārta
A2 - Zavadska, Dace
A2 - Laivacuma, Sniedze
A2 - Rudzāte, Aleksandra
A2 - Stoldere, Diāna
A2 - Barzdina, Arta
A2 - Bārzdiņa, Elza
A2 - Madelane, Monta
A2 - Balode, Anda
A2 - Grope, Ilze
A2 - Meiere, Anija
A2 - Nokalna, Ieva
A2 - Pavare, Jana
A2 - Pucuka, Zanda
A2 - Urbane, Urzula Nora
A2 - Selecka, Katrina
N1 - Funding Information:
UKHSA funded the metagenomics and HAdV sequencing. We thank A. Nathwani for helpful discussions. We acknowledge the considerable contribution from the GOSH microbiology laboratory. We thank the medical students who contributed to the DIAMOND consortium. All research at GOSH and UCL GOSH Institute of Child Health is made possible by the NIHR GOSH Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research (NIHR), the UKRI or the Department of Health and Social Care. The work was part funded by the NIHR Blood and Transplant Research Unit in Genomics to Enhance Microbiology Screening (GEMS), the National Institute for Health and Care Research (CO-CIN-01) or jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). S. Morfopoulou is funded by a W.T. Henry Wellcome fellowship (206478/Z/17/Z). S.B. and O.E.T.M. are funded by the NIHR Blood and Transplant Research Unit (GEMS). M.M.M. and M.L. are supported in part by the NIHR Biomedical Research Centre of Imperial College NHS Trust. J.B. receives NIHR Senior Investigator Funding. M.N. and J.B. are supported by the Wellcome Trust (207511/Z/17/Z and 203268/Z/16/Z). M.N., J.B. and G.P. are supported by the NIHR University College London Hospitals Biomedical Research Centre. P. Simmonds is supported by the NIHR (NIHR203338). T.S.J. is grateful for funding from the Brain Tumour Charity, Children with Cancer UK, GOSH Children’s Charity, Olivia Hodson Cancer Fund, Cancer Research UK and the NIHR. DIAMONDS is funded by the European Union (Horizon 2020; grant 848196). PERFORM was funded by the European Union (Horizon 2020; grant 668303).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/3/30
Y1 - 2023/3/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85151469478&partnerID=8YFLogxK
U2 - 10.1038/s41586-023-06003-w
DO - 10.1038/s41586-023-06003-w
M3 - Article
C2 - 36996872
AN - SCOPUS:85151469478
SN - 0028-0836
VL - 617
SP - 564
EP - 573
JO - Nature
JF - Nature
IS - 7961
ER -
