BTN3A3 evasion promotes the zoonotic potential of influenza A viruses

Rute Maria Pinto, Siddharth Bakshi, Spyros Lytras, Mohammad Khalid Zakaria, Simon Swingler, Julie C. Worrell, Vanessa Herder, Kerrie E. Hargrave, Margus Varjak, Natalia Cameron-Ruiz, Mila Collados Rodriguez, Mariana Varela, Arthur Wickenhagen, Colin Loney, Yanlong Pei, Joseph Hughes, Elise Valette, Matthew L. Turnbull, Wilhelm Furnon, Quan Gu, Lauren Orr, Aislynn Taggart, Ola Diebold, Chris Davis, Chris Boutell, Finn Grey, Edward Hutchinson, Paul Digard, Isabella Monne, Sarah K. Wootton, Megan K. L. MacLeod, Sam J. Wilson and Massimo Palmarini ()
Additional contact information
Rute Maria Pinto: MRC–University of Glasgow Centre for Virus Research
Siddharth Bakshi: MRC–University of Glasgow Centre for Virus Research
Spyros Lytras: MRC–University of Glasgow Centre for Virus Research
Mohammad Khalid Zakaria: MRC–University of Glasgow Centre for Virus Research
Simon Swingler: MRC–University of Glasgow Centre for Virus Research
Julie C. Worrell: University of Glasgow
Vanessa Herder: MRC–University of Glasgow Centre for Virus Research
Kerrie E. Hargrave: University of Glasgow
Margus Varjak: MRC–University of Glasgow Centre for Virus Research
Natalia Cameron-Ruiz: MRC–University of Glasgow Centre for Virus Research
Mila Collados Rodriguez: MRC–University of Glasgow Centre for Virus Research
Mariana Varela: MRC–University of Glasgow Centre for Virus Research
Arthur Wickenhagen: MRC–University of Glasgow Centre for Virus Research
Colin Loney: MRC–University of Glasgow Centre for Virus Research
Yanlong Pei: University of Guelph
Joseph Hughes: MRC–University of Glasgow Centre for Virus Research
Elise Valette: MRC–University of Glasgow Centre for Virus Research
Matthew L. Turnbull: MRC–University of Glasgow Centre for Virus Research
Wilhelm Furnon: MRC–University of Glasgow Centre for Virus Research
Quan Gu: MRC–University of Glasgow Centre for Virus Research
Lauren Orr: MRC–University of Glasgow Centre for Virus Research
Aislynn Taggart: MRC–University of Glasgow Centre for Virus Research
Ola Diebold: University of Edinburgh
Chris Davis: MRC–University of Glasgow Centre for Virus Research
Chris Boutell: MRC–University of Glasgow Centre for Virus Research
Finn Grey: University of Edinburgh
Edward Hutchinson: MRC–University of Glasgow Centre for Virus Research
Paul Digard: University of Edinburgh
Isabella Monne: Istituto Zooprofilattico Sperimentale delle Venezie (IZSVe)
Sarah K. Wootton: University of Guelph
Megan K. L. MacLeod: University of Glasgow
Sam J. Wilson: MRC–University of Glasgow Centre for Virus Research
Massimo Palmarini: MRC–University of Glasgow Centre for Virus Research

Nature, 2023, vol. 619, issue 7969, 338-347

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41586-023-06261-8

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