TY - JOUR
T1 - N-Glycolylneuraminic Acid Binding of Avian and Equine H7 Influenza A Viruses
AU - Spruit, Cindy M.
AU - Zhu, Xueyong
AU - Tomris, Ilhan
AU - Ríos-Carrasco, María
AU - Han, Alvin X.
AU - Broszeit, Frederik
AU - van der Woude, Roosmarijn
AU - Bouwman, Kim M.
AU - Luu, Michel M. T.
AU - Matsuno, Keita
AU - Sakoda, Yoshihiro
AU - Russell, Colin A.
AU - Wilson, Ian A.
AU - Boons, Geert-Jan
AU - de Vries, Robert P.
N1 - Funding Information: R.P.D.V. is a recipient of an ERC Starting Grant from the European Commission (no. 802780) and a Beijerinck Premium of the Royal Dutch Academy of Sciences. C.A.R. and A.X.H. are supported by an ERC Consolidator Grant from the European Commission (no. 818353). Synthesis and microarray analyses were funded by a grant from the Netherlands Organization for Scientific Research (NWO TOPPUNT 718.015.003) to G.-J.B. This work was funded in part by the Bill and Melinda Gates Foundation (grant no. OPP1170236) to I.A.W. X-ray data were collected at the APS beamline 23ID-D (GM/CA CAT). The use of the APS was supported by the U.S. Department of Energy (DOE), Basic Energy Sciences, Office of Science, under contract no. DE-AC02-06CH11357. Funding Information: We thank the Department of Equine Sciences and the Department of Farm Animal Health of Utrecht University for supplying erythrocytes. We thank Andrea Gr?ne and H?l?ne Verheije from the Division of Pathology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, for providing paraffin-embedded tissues. We thank Eva Klaver and Nigel Kroone for their technical assistance. R.P.D.V. is a recipient of an ERC Starting Grant from the European Commission (no. 802780) and a Beijerinck Premium of the Royal Dutch Academy of Sciences. C.A.R. and A.X.H. are supported by an ERC Consolidator Grant from the European Commission (no. 818353). Synthesis and microarray analyses were funded by a grant from the Netherlands Organization for Scientific Research (NWO TOPPUNT 718.015.003) to G.-J.B. This work was funded in part by the Bill and Melinda Gates Foundation (grant no. OPP1170236) to I.A.W. X-ray data were collected at the APS beamline 23ID-D (GM/CA CAT). The use of the APS was supported by the U.S. Department of Energy (DOE), Basic Energy Sciences, Office of Science, under contract no. DE-AC02-06CH11357. Publisher Copyright: Copyright © 2022 Spruit et al.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Influenza A viruses (IAV) initiate infection by binding to glycans with terminal sialic acids on the cell surface. Hosts of IAV variably express two major forms of sialic acid, N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc). NeuGc is produced in most mammals, including horses and pigs, but is absent in humans, ferrets, and birds. The only known naturally occurring IAV that exclusively bind NeuGc are extinct highly pathogenic equine H7N7 viruses. We determined the crystal structure of a representative equine H7 hemagglutinin (HA) in complex with NeuGc and observed high similarity in the receptor-binding domain with an avian H7 HA. To determine the molecular basis for NeuAc and NeuGc specificity, we performed systematic mutational analyses, based on the structural insights, on two distant avian H7 HAs and an H15 HA. We found that the A135E mutation is key for binding a2,3-linked NeuGc but does not abolish NeuAc binding. The additional mutations S128T, I130V, T189A, and K193R converted the specificity from NeuAc to NeuGc. We investigated the residues at positions 128, 130, 135, 189, and 193 in a phylogenetic analysis of avian and equine H7 HAs. This analysis revealed a clear distinction between equine and avian residues. The highest variability was observed at key position 135, of which only the equine glutamic acid led to NeuGc binding. These results demonstrate that genetically distinct H7 and H15 HAs can be switched from NeuAc to NeuGc binding and vice versa after the introduction of several mutations, providing insights into the adaptation of H7 viruses to NeuGc receptors. IMPORTANCE Influenza A viruses cause millions of cases of severe illness and deaths annually. To initiate infection and replicate, the virus first needs to bind to a structure on the cell surface, like a key fitting in a lock. For influenza A viruses, these “keys” (receptors) on the cell surface are chains of sugar molecules (glycans). The terminal sugar on these glycans is often either N-acetylneuraminic acid (NeuAc) or N-glycolylneuraminic acid (NeuGc). Most influenza A viruses bind NeuAc, but a small minority bind NeuGc. NeuGc is present in species like horses, pigs, and mice but not in humans, ferrets, and birds. Here, we investigated the molecular determinants of NeuGc specificity and the origin of viruses that bind NeuGc.
AB - Influenza A viruses (IAV) initiate infection by binding to glycans with terminal sialic acids on the cell surface. Hosts of IAV variably express two major forms of sialic acid, N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc). NeuGc is produced in most mammals, including horses and pigs, but is absent in humans, ferrets, and birds. The only known naturally occurring IAV that exclusively bind NeuGc are extinct highly pathogenic equine H7N7 viruses. We determined the crystal structure of a representative equine H7 hemagglutinin (HA) in complex with NeuGc and observed high similarity in the receptor-binding domain with an avian H7 HA. To determine the molecular basis for NeuAc and NeuGc specificity, we performed systematic mutational analyses, based on the structural insights, on two distant avian H7 HAs and an H15 HA. We found that the A135E mutation is key for binding a2,3-linked NeuGc but does not abolish NeuAc binding. The additional mutations S128T, I130V, T189A, and K193R converted the specificity from NeuAc to NeuGc. We investigated the residues at positions 128, 130, 135, 189, and 193 in a phylogenetic analysis of avian and equine H7 HAs. This analysis revealed a clear distinction between equine and avian residues. The highest variability was observed at key position 135, of which only the equine glutamic acid led to NeuGc binding. These results demonstrate that genetically distinct H7 and H15 HAs can be switched from NeuAc to NeuGc binding and vice versa after the introduction of several mutations, providing insights into the adaptation of H7 viruses to NeuGc receptors. IMPORTANCE Influenza A viruses cause millions of cases of severe illness and deaths annually. To initiate infection and replicate, the virus first needs to bind to a structure on the cell surface, like a key fitting in a lock. For influenza A viruses, these “keys” (receptors) on the cell surface are chains of sugar molecules (glycans). The terminal sugar on these glycans is often either N-acetylneuraminic acid (NeuAc) or N-glycolylneuraminic acid (NeuGc). Most influenza A viruses bind NeuAc, but a small minority bind NeuGc. NeuGc is present in species like horses, pigs, and mice but not in humans, ferrets, and birds. Here, we investigated the molecular determinants of NeuGc specificity and the origin of viruses that bind NeuGc.
KW - Glycan array
KW - H7
KW - Hemagglutinin
KW - Influenza
KW - N-glycolylneuraminic acid
KW - NeuGc
KW - Receptor-ligand interaction
KW - Sialic acid
UR - http://www.scopus.com/inward/record.url?scp=85126126705&partnerID=8YFLogxK
U2 - https://doi.org/10.1128/jvi.02120-21
DO - https://doi.org/10.1128/jvi.02120-21
M3 - Article
C2 - 35044215
SN - 0022-538X
VL - 96
JO - Journal of Virology
JF - Journal of Virology
IS - 5
M1 - e02120-21
ER -