Genomic investigations of unexplained acute hepatitis in children

Morfopoulou, S. et al. (2023) Genomic investigations of unexplained acute hepatitis in children. Nature, 617(7961), pp. 564-573. (doi: 10.1038/s41586-023-06003-w) (PMID:36996872)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gunson, Dr Rory and Shepherd, Dr Samantha and Ho, Dr Antonia and Thomson, Professor Emma and Palmarini, Professor Massimo and Pollock, Dr Louisa
• Authors: Morfopoulou, S., Buddle, S., Torres Montaguth, O. E., Atkinson, L., Guerra-Assunção, J. A., Moradi Marjaneh, M., Zennezini Chiozzi, R., Storey, N., Campos, L., Hutchinson, J. C., Counsell, J. R., Pollara, G., Roy, S., Venturini, C., Antinao Diaz, J. F., Siam, A.’a., Tappouni, L. J., Asgarian, Z., Ng, J., Hanlon, K. S., Lennon, A., McArdle, A., Czap, A., Rosenheim, J., Andrade, C., Anderson, G., Lee, J. C. D., Williams, R., Williams, C. A., Tutill, H., Bayzid, N., Martin Bernal, L. M., Macpherson, H., Montgomery, K.-A., Moore, C., Templeton, K., Neill, C., Holden, M., Gunson, R., Shepherd, S. J., Shah, P., Cooray, S., Voice, M., Steele, M., Fink, C., Whittaker, T. E., Santilli, G., Gissen, P., Kaufer, B. B., Reich, J., Andreani, J., Simmonds, P., Alrabiah, D. K., Castellano, S., Chikowore, P., Odam, M., Rampling, T., Houlihan, C., Hoschler, K., Talts, T., Celma, C., Gonzalez, S., Gallagher, E., Simmons, R., Watson, C., Mandal, S., Zambon, M., Chand, M., Hatcher, J., De, S., Baillie, K., Semple, M. G., Bellos, E., Broderick, C., Channon-Wells, S., De, T., D’Souza, G., Elorrieta, L. E., Estrada-Rivadeneyra, D., Galassini, R., Habgood-Coote, D., Hamilton, S., Jackson, H., Kavanagh, J., Marjaneh, M. M., Menikou, S., Nichols, S., Nijman, R., Patel, H., Pennisi, I., Powell, O., Reid, R., Vito, O., Whittaker, E., Wilson, C., Womersley, R., Abdulla, A., Darnell, S., Mustafa, S., Georgiou, P., Manzano, J.-R., Moser, N., Carter, M., Tibby, S., Cohen, J., Davis, F., Kenny, J., Wellman, P., White, M., Fish, M., Jennings, A., Shankar-Hari, , Fidler, K., Agranoff, D., Richmond, V., Seal, M., Faust, S., Owen, D., Ensom, R., McKay, S., Mondo, D., Shaji, M., Schranz, R., Rughnani, P., Anpananthar, A., Liebeschuetz, S., Riddell, A., Khalid, N., Malcolm, I. L., Simagan, T., Peters, M., Bamford, A., Pathan, N., Daubney, E., White, D., Heightman, M., Eisen, S., Segal, T., Wellings, L., Drysdale, S. B., Branch, N., Hamzah, L., Jarman, H., Nyirenda, M., Capozzi, L., Gardiner, E., Moots, R., Nasher, M., Hanson, A., Linforth, M., O’Riordan, S., Ellis, D., Deep, A., Caro, I., Shackley, F., Bellini, A., Gormley, S., Neshat, S., Scholefield, B. J., Robbins, C., Winmill, H., Paulus, S. C., Pollard, A. J., Hopton, S., Miller, D., Oliver, Z., Beer, S., Ward, B., Shrestha, S., Gurung, M., Amatya, P., Pokhrel, B., Bijukchhe, S. M., Lubinda, T., Kelly, S., O’Reilly, P., Martinón-Torres, F., Salas, A., González, F. Á., Bello, X., García, M. B., Carnota, S., Cebey-López, M., Curras-Tuala, M. J., Suárez, C. D., Vicente, L. G., Gómez-Carballa, A., Rial, J. G., Iglesias, P. L., Martinón-Torres, N., Sánchez, J. M. M., Pérez, B. M., Pardo-Seco, J., Rodríguez, L. P., Pischedda, S., Vázquez, S. R., Calle, I. R., Rodríguez-Tenreiro, C., Redondo-Collazo, L., Ora, M. S., Fernández, S. S., Trasorras, C. S., Iglesias, M. V., Carrol, E. D., Cocklin, E., Khanijau, A., Lenihan, R., Lewis-Burke, N., Newal, K., Romaine, S., Tsolia, M., Eleftheriou, I., Spyridis, N., Tambouratzi, M., Maritsi, D., Marmarinos, A., Xagorari, M., Panagiota, L., Aggelos, P., Karolina, A., Charalambos, G., Markos, M., Michalis, V., Ioanna, S., Emonts, M., Lim, E., Isaacs, J., Bell, K., Crulley, S., Fabian, D., Thomson, E., Miller, C., Bell, A., van der Velden, F. J. S., Shenton, G., Price, A., Treloar, O., Thomas, D., Rojo, P., Epalza, C., Villaverde, S., Márquez, S., Gijón, M., Machín, F., Cabello, L., Hernández, I., Gutiérrez, L., Manzanares, Á., Kuijpers, T., van de Kuip, M., van Furth, M., van den Berg, M., Biesbroek, G., Verkuil, F., van der Zee, C., Pajkrt, D., van Hensbroek, M. B., Schonenberg, D., Gruppen, M., Nagelkerke, S., Jansen, M. H., Goetschalckx, I., Romani, L., Luca, M. D., Chiurchiù, S., Giuseppe, M. D., Vermont, C. L., Moll, H. A., Borensztajn, D. M., Hagedoorn, N. N., Tan, C., Zachariasse, J., Dik, W., Shen, C.-F., Zavadska, D., Laivacuma, S., Rudzate, A., Stoldere, D., Barzdina, A., Barzdina, E., Laivacuma, S., Madelane, M., Gravele, D., Svile, D., Basmaci, R., Lachaume, N., Bories, P., Tkhayat, R. B., Chériaux, L., Davoust, J., Ong, K.-T., Cotillon, M., de Groc, T., Le, S., Vergnault, N., Sée, H., Cohen, L., de Tugny, A., Danekova, N., Mommert-Tripon, M., Brengel-Pesce, K., Pokorn, M., Kolnik, M., Avcin, T., Avramoska, T., Bahovec, N., Bogovic, P., Kitanovski, L., Nahtigal, M., Papst, L., Srovin, T. P., Strle, F., Srpcic, A., Vincek, K., van der Flier, M., Tissing, W. J. E., Wösten-van Asperen, R. M., Vastert, S. J., Vijlbrief, D. C., Bont, L. J., Wolfs, T. F. W., Beudeker, C. R., Agyeman, P., Schlapbach, L., Aebi, C., Usman, M., Schlüchter, S., Wyss, V., Schöbi, N., Zimmermann, E., Weber, K., Giannoni, E., Stocker, M., Posfay-Barbe, K. M., Heininger, U., Bernhard-Stirnemann, S., Niederer-Loher, A., Kahlert, C., Natalucci, G., Relly, C., Riedel, T., Berger, C., Holden, J., Calvo-Bado, L., Evans, B., Stevens, J., Matthews, P., Billing, K., Zenz, W., Binder, A., Kohlmaier, B., Kohlfürst, D. S., Schweintzger, N. A., Zurl, C., Hösele, S., Leitner, M., Pölz, L., Rusu, A., Rajic, G., Stoiser, B., Strempfl, M., Sagmeister, M. G., Bauchinger, S., Benesch, M., Ceolotto, A., Eber, E., Gallistl, S., Haidl, H., Hauer, A., Hude, C., Kapper, A., Keldorfer, M., Löffler, S., Niedrist, T., Pilch, H., Pfleger, A., Pfurtscheller, K., Rödl, S., Skrabl-Baumgartner, A., Strenger, V., Wallner, E., Tempel, D., van Keulen, D., Strijbosch, A. M., Tauchert, M. K., von Both, U., Kolberg, L., Schmied, P., Alba-Alejandre, I., Danhauser, K., Haas, N., Hoffmann, F., Griese, M., Feuchtinger, T., Juranek, S., Kappler, M., Lurz, E., Maier, E., Reiter, K., Schoen, C., Schroepf, S., Yeung, S., Dewez, M., Bath, D., Fitchett, E., Cresswell, F., Cunnington, A., Herberg, J., Kaforou, M., Wright, V., Baumard, L., Hoggart, C., Hourmat, S., Maconochie, I., Lin, N., Paz, I. P., Ali, L., Jorgensen, R., Persand, S., Stevens, M., Kim, E., Pierce, B., Dudley, J., Tavliavini, E., Liu, C.-C., Wang, S.-M., Farto, C. B., Barral-Arca, R., Castro, M. B., Balode, A., Deksne, D., Grope, I., Meiere, A., Nokalna, I., Pavare, J., Pucuka, Z., Selecka, K., Sidorova, A., Urbane, U. N., Usuf, E., Bojang, K., Zaman, S. M. A., Secka, F., Anderson, S., Sarr, A. R., Saidykhan, M., Darboe, S., Ceesay, S., D’alessandro, U., Schlapbach, L. J., Paulus, S., Jennings, R., Johnston, J., Leigh, S., Newall, K., Marmarinos, A., Syggelou, K., Baumgart, H., Benesch, M., Gores, G., Krenn, L., Nordberg, G., Sperl, M., Stampfer, L., Till, H., Trobisch, A., Dewez, J. E., Hibberd, M., Miners, A., Nijman, R., Wedderburn, C., Meierford, A., Leurent, B., de Groot, R., van der Flier, M., de Jonge, M. I., van Aerde, K., Alkema, W., van den Broek, B., Gloerich, J., van Gool, A. J., Henriet, S., Huijnen, M., Philipsen, R., Willems, E., Gerrits, G. P. J. M., van Leur, M., Heidema, J., de Haan, L., Miedema, C. J., Neeleman, C., Obihara, C. C., Tramper-Stranders, G. A., Kandasamy, R., Paulus, S., Carter, M. J., O’Connor, D., Bibi, S., Kelly, D. F., Thorson, S., Ansari, I., Murdoch, D. R., Valentine, L., Allen, K., Chan, A., Devine, K., King, S., McAlinden, P., McDonald, S., McDonnell, A., Pickering, A., Wood, A., Wallia, D., Woodsford, P., Baxter, F., Rhodes, M., Agbeko, R., Mackerness, C., Baas, B., Kloosterhuis, L., Oosthoek, W., Arif, T., Bennet, J., Collings, K., van der Giessen, I., Martin, A., Rashid, A., Rowlands, E., de Vries, G., van der Velden, F., Martin, M., Mistry, R., Zwerenz, M., Buschbeck, J., Bidlingmaier, C., Binder, V., Keil, J., Muench, G., Mallet, F., Pachot, A., Mommert, M., Pokorn, M., Prunk, P., Osterman, V., Kuijpers, T., Jongerius, I., van den Berg, J. M., Schonenberg, D., Barendregt, A. M., Pajkrt, D., van der Kuip, M., van Furth, A. M., Sprenkeler, E., Zandstra, J., van Mierlo, G., Geissler, J., Carson, G., Openshaw, P. J. M., Dunning, J., Merson, L., Russell, C. D., Dorward, D., Tedder, R. S., Khoo, S., Turtle, L. C. W., Solomon, T., Ijaz, S., Fletcher, T., Palmarini, M., Ho, A. Y.H., Price, N., de Silva, T., Donohue, C., Hardwick, H., Oosthuyzen, W., Obosi, L., Clohisey, S., Law, A., Norris, L., Tait, S., Wham, M., Clark, R., Coutts, A., Donelly, L., Fawkes, A., Gilchrist, T., Hafezi, K., MacGillivray, L., Maclean, A., McCafferty, S., Morrice, K., Murphy, L., Wrobel, N., McDonald, S. E., Shaw, V., Armstrong, J. A., Lett, L., Henderson, P., Pollock, L., Kishore, S., Brotherton, H., Armstrong, L., Mita, A., Dall, A., Bohmova, K., Logan, S., Gannon, L., Agwuh, K., Chukkambotla, S., DuRand, I., Fullerton, D., Garg, S., Graham, C., Hartshorn, S., Hodgson, L., Jennings, P., Koshy, G., Leiner, T., Limb, J., Little, J., Matovu, E., McGill, F., Morris, C., Morrice, J., Price, D., Reschreiter, H., Reynolds, T., Whittaker, P., Tayler, R., Irving, C., Ramsay, M., Millar, M., Milligan, B., Hickey, N., Connon, M., Ward, C., Beveridge, L., MacFarlane, S., Leitch, K., Bell, C., Finlayson, L., Dawson, J., Candlish, J., McGenily, L., Roome, T., Diaba, C., Player, J., Powell, N., Howman, R., Burling, S., Floyd, S., Farmer, S., Ferguson, S., Hope, S., Rubick, L., Swingler, R., Collins, E., Spencer, C., Jones, A., Wilson, B., Armstrong, D., Birt, M., Dickinson, H., Harper, R., Martin, D., Roff, A., Mills, S., Martin, J., Ushiro-Lumb, I., Noursadeghi, M., Deheragoda, M., Hadzic, N., Grammatikopoulos, T., Brown, R., Kelgeri, C., Thalassinos, K., Waddington, S. N., Jacques, T. S., Thomson, E., Levin, M., Brown, J. R., and Breuer, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Nature
• Publisher: Nature Research
• ISSN: 0028-0836
• ISSN (Online): 1476-4687
• Published Online: 30 March 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Nature 617(7961): 564-573
• Publisher Policy: Reproduced under a Creative Commons License