RT Journal Article
SR Electronic
T1 Zoonotic avian influenza viruses evade human BTN3A3 restriction
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.14.496196
DO 10.1101/2022.06.14.496196
A1 Rute Maria Pinto
A1 Siddharth Bakshi
A1 Spyros Lytras
A1 Mohammad Khalid Zakaria
A1 Simon Swingler
A1 Julie C Worrell
A1 Vanessa Herder
A1 Margus Varjak
A1 Natalia Cameron-Ruiz
A1 Mila Collados Rodriguez
A1 Mariana Varela
A1 Arthur Wickenhagen
A1 Colin Loney
A1 Yanlong Pei
A1 Joseph Hughes
A1 Elise Valette
A1 Matthew L Turnbull
A1 Wilhelm Furnon
A1 Kerrie E Hargrave
A1 Quan Gu
A1 Lauren Orr
A1 Aislynn Taggart
A1 Chris Boutell
A1 Finn Grey
A1 Edward Hutchinson
A1 Paul Digard
A1 Isabella Monne
A1 Sarah K Wootton
A1 Megan K L MacLeod
A1 Sam J Wilson
A1 Massimo Palmarini
YR 2022
UL http://biorxiv.org/content/early/2022/06/15/2022.06.14.496196.abstract
AB Cross-species transmission of avian influenza A viruses (IAVs) into humans could represent the first step of a future pandemic1. Multiple factors limiting the spillover and adaptation of avian IAVs in humans have been identified, but they are not sufficient to explain which virus lineages are more likely to cross the species barrier1,2. Here, we identified human BTN3A33 (butyrophilin subfamily 3 member A3) as a potent inhibitor of avian but not human IAVs. We determined that BTN3A3 is constitutively expressed in human airways and its antiviral activity evolved in primates. We show that BTN3A3 restriction acts at the early stages of virus replication by inhibiting avian IAV vRNA transcription. 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, several serotypes of avian IAVs that spilled over into humans in recent decades 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 structure4. Importantly, we identified more than 150 avian IAV lineages with a BTN3A3-resistant genotype. In conclusion, sensitivity or resistance to BTN3A3 is another factor to consider in the risk assessment of the zoonotic potential of avian influenza viruses.Competing Interest StatementThe authors have declared no competing interest.