| Autor: |
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, 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, 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, DIAMONDS consortium, ISARIC 4C Investigators, PERFORM Consortium, Breuer, Judith |
| Přispěvatelé: |
University of St Andrews. St Andrews Bioinformatics Unit, University of St Andrews. Infection and Global Health Division, University of St Andrews. Biomedical Sciences Research Complex, University of St Andrews. School of Medicine |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Popis: |
Funding: UKHSA funded the metagenomics and HAdV sequencing. 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). 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. Publisher PDF |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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