Genetic determinants of receptor-binding preference and zoonotic potential of H9N2 avian influenza viruses

Peacock, T. P., Sealy, J. E., Harvey, W. T., Benton, D. J., Reeve, R. and Iqbal, M. (2021) Genetic determinants of receptor-binding preference and zoonotic potential of H9N2 avian influenza viruses. Journal of Virology, 95(5), e01651-20. (doi: 10.1128/JVI.01651-20) (PMID:33268517)

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Abstract

Receptor recognition and binding is the first step of viral infection and a key determinant of host specificity. The inability of avian influenza viruses to effectively bind human-like sialylated receptors is a major impediment to their efficient transmission in humans and pandemic capacity. Influenza H9N2 viruses are endemic in poultry across Asia and parts of Africa where they occasionally infect humans and are therefore considered viruses with zoonotic potential. We previously described H9N2 viruses, including several isolated from human zoonotic cases, showing a preference for human-like receptors. Here we take a mutagenesis approach, making viruses with single or multiple substitutions in H9 haemagglutinin and test binding to avian and human receptor analogues using biolayer interferometry. We determine the genetic basis of preferences for alternative avian receptors and for human-like receptors, describing amino acid motifs at positions 190, 226 and 227 that play a major role in determining receptor specificity, and several other residues such as 159, 188, 193, 196, 198 and 225 that play a smaller role. Furthermore, we show changes at residues 135, 137, 147, 157, 158, 184, 188, and 192 can also modulate virus receptor avidity and that substitutions that increased or decreased the net positive charge around the haemagglutinin receptor-binding site show increases and decreases in avidity, respectively. The motifs we identify as increasing preference for the human-receptor will help guide future H9N2 surveillance efforts and facilitate our understanding of the emergence of influenza viruses with increased zoonotic potential.

Item Type:Articles
Additional Information:This research was supported by the Biotechnology and Biological Sciences Research Council under grants BBS/E/00001759 (TPP), BBS/E/I/00001708 (JES), BBS/E/I/00007031 (MI), BBS/E/I/00007035 (MI), BBS/E/I/00007038 (MI), BBS/E/I/00007039 (MI), BB/L018853/1 (MI), BB/S013792/1 (MI), BB/L004828/1 (RR), BB/P004202/1 (RR) and BB/R012679/1 (MI, RR), Zoonoses and Emerging Livestock systems grant number BB/L018853/1 and BB/S013792/1, the GCRF One Health Poultry Hub grant number BB/S011269/1 (MI, JES) and the Medical Research Council under grant numbers MR/J50032X/1 (1097258) and MR/R024758/1 (WTH). The Francis Crick Institute receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Reeve, Dr Richard and Harvey, Dr William
Authors: Peacock, T. P., Sealy, J. E., Harvey, W. T., Benton, D. J., Reeve, R., and Iqbal, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:Journal of Virology
Publisher:American Society for Microbiology
ISSN:0022-538X
ISSN (Online):1098-5514
Published Online:02 December 2020
Copyright Holders:Copyright © 2021 Peacock et al.
First Published:First published in Journal of Virology 95(5): e01651-20
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
171417An effective vaccination programme for the eradication of foot-and-mouth disease from IndiaRichard ReeveBiotechnology and Biological Sciences Research Council (BBSRC)BB/L004828/1 1805Institute of Biodiversity, Animal Health and Comparative Medicine
173099Mathematical Theory and Biological Applications of DiversityRichard ReeveBiotechnology and Biological Sciences Research Council (BBSRC)BB/P004202/1Institute of Biodiversity, Animal Health and Comparative Medicine
190394MRC Doctoral Training Grant 2011-2015Mary Beth KneafseyMedical Research Council (MRC)MR/J50032X/1Research and Innovation Services
302632Using a comparative One Health approach to investigate the structural basis of antigenic variation among human and avian influenza virusesJill PellMedical Research Council (MRC)MR/R024758/1Institute of Biodiversity, Animal Health and Comparative Medicine