BTN3A3 evasion promotes the zoonotic potential of influenza A viruses

Pinto, R. M. et al. (2023) BTN3A3 evasion promotes the zoonotic potential of influenza A viruses. Nature, 619(7969), pp. 338-347. (doi: 10.1038/s41586-023-06261-8) (PMID:37380775)

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Spillover events of avian influenza A viruses (IAVs) to humans could represent the first step in a future pandemic1. Several factors that limit the transmission and replication of avian IAVs in mammals have been identified. There are several gaps in our understanding to predict which virus lineages are more likely to cross the species barrier and cause disease in humans1. Here, we identified human BTN3A3 (butyrophilin subfamily 3 member A3)2 as a potent inhibitor of avian IAVs but not human IAVs. We determined that BTN3A3 is expressed in human airways and its antiviral activity evolved in primates. We show that BTN3A3 restriction acts primarily at the early stages of the virus life cycle by inhibiting avian IAV RNA replication. We identified residue 313 in the viral nucleoprotein (NP) as the genetic determinant of BTN3A3 sensitivity (313F or, rarely, 313L in avian viruses) or evasion (313Y or 313V in human viruses). However, avian IAV serotypes, such as H7 and H9, that spilled over into humans also evade BTN3A3 restriction. In these cases, BTN3A3 evasion is due to substitutions (N, H or Q) in NP residue 52 that is adjacent to residue 313 in the NP structure3. Thus, sensitivity or resistance to BTN3A3 is another factor to consider in the risk assessment of the zoonotic potential of avian influenza viruses.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Furnon, Dr Wilhelm and Swingler, Dr Simon and Turnbull, Dr Matthew and Loney, Mr Colin and Wilson, Professor Sam and Wickenhagen, Mr Arthur and Palmarini, Professor Massimo and Boutell, Dr Chris and Lytras, Spyros and Taggart, Ms Aislynn and Davis, Dr Chris and Herder, Dr Vanessa and Hargrave, Dr Kerrie and Zakaria, Dr Mohammad Khalid and Varjak, Dr Margus and Gu, Dr Quan and Bakshi, Dr Siddharth and Macleod, Dr Megan and Hutchinson, Dr Edward and Collados Rodriguez, Dr Milagros and Digard, Professor Paul and Worrell, Dr Julie and Cameron Ruiz, Natalia and Hughes, Dr Joseph and Orr, Miss Lauren and Pinto, Dr Rute and Varela, Dr Mariana
Authors: Pinto, R. M., Bakshi, S., Lytras, S., Zakaria, M. K., Swingler, S., Worrell, J. C., Herder, V., Hargrave, K. E., Varjak, M., Cameron-Ruiz, N., Collados Rodriguez, M., Varela, M., Wickenhagen, A., Loney, C., Pei, Y., Hughes, J., Valette, E., Turnbull, M. L., Furnon, W., Gu, Q., Orr, L., Taggart, A., Diebold, O., Davis, C., Boutell, C., Grey, F., Hutchinson, E., Digard, P., Monne, I., Wootton, S. K., MacLeod, M. K.L., Wilson, S. J., and Palmarini, M.
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 (Online):1476-4687
Published Online:28 June 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Nature 619(7969): 338-347
Publisher Policy:Reproduced in accordance with the publisher copyright policy
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172630010Innate Immunity and Host Species Barriers (Programme 7)Massimo PalmariniMedical Research Council (MRC)MC_UU_12014/10III - Centre for Virus Research
172630011Innate Immunity and Host Species Barriers (Programme 7)Sam WilsonMedical Research Council (MRC)MC_UU_12014/10III - Centre for Virus Research
301049Host determinants of disease outcomes in arboviral infectionsMassimo PalmariniWellcome Trust (WELLCOTR)206369/Z/17/ZIII - Centre for Virus Research
302947Identification of interferon stimulated genes that restrict cross-species transmission of influenza A virusSam WilsonBiotechnology and Biological Sciences Research Council (BBSRC)BB/S00114X/1III - Centre for Virus Research
172398Functional investigations of the influenza virus proteomeEdward HutchinsonMedical Research Council (MRC)MR/N008618/1III-MRC-GU Centre for Virus Research
312928The role and regulation of RNA binding proteins in plant immunity and infectionEdward HutchinsonMedical Research Council (MRC)MR/V035789/1III - Centre for Virus Research
302383Communication between lung immune and stromal cells drives tissue protective immune memoryMegan MacLeodWellcome Trust (WELLCOTR)210703/Z/18/ZIII - Immunology
172630009Analysing the Role of Ubiquitin and Ubiquitin-like Modification During Herpesvirus Infection and Host Immunity (Programme 6)Chris BoutellMedical Research Council (MRC)MC_UU_12014/5III - Centre for Virus Research
172630014Cross-Cutting Programme – Viral Genomics and Bioinformatics (Programme 9)David RobertsonMedical Research Council (MRC)MC_UU_12014/12III - Centre for Virus Research
172630Quinquennial Core FundsMassimo PalmariniMedical Research Council (MRC)MC_UU_12014/9III-MRC-GU CVR Support Services