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Event: 2158

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Influenza A Virus (IAV) binds sialic acid glycan receptor

Short name

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IAV binds receptor

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Biological Context

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Level of Biological Organization
Molecular

Cell term

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Cell term
epithelial cell

Organ term

Organ term
respiratory tract epithelium

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
receptor binding		occurrence

Key Event Overview

AOPs Including This Key Event

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AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
IAV infection proliferation	MolecularInitiatingEvent	Jessica Resnick (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI
chicken	Gallus gallus	High	NCBI
Pig	Pig	High	NCBI
mouse	Mus musculus	High	NCBI
cat	Felis catus	Moderate	NCBI
dog	Canis lupus familiaris	Moderate	NCBI
ferret	Mustela putorius furo	High	NCBI
Syrian hamster	Mesocricetus auratus	High	NCBI
guinea pig	Cavia porcellus	High	NCBI
rhesus macaque	Macaca mulatta	High	NCBI

Life Stages

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Life stage	Evidence
Adult, reproductively mature	High
During development and at adulthood	High

Sex Applicability

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Term	Evidence
Mixed	High

Key Event Description

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Sialic acid was one of the first viral receptors identified⁵. Humans have 6 sialyl transferases that catalyze the addition of Sia with an a2,3 linkage to terminal galactose residues and 2 that catalyze the addition of an a2,6 linkage to terminal galactose residues⁶.

The HA receptor of the IAV attaches to the surface of the host cell via glycoconjugates that contain terminal sialic acid residues. The virus then “scans” the surface of the cell for the correct receptor, using its NA to remove nonproductive HA associations. The exact receptor is currently unknown however human influenza viruses preferentially bind sialic acid linked to galactose by a2,6 linkage, while avian influenza viruses prefer a2,3 linkages¹. However, most viruses are not this dichotomous and the ability to bind sialic acid is more of a spectrum². Additionally, the human respiratory tract contains both types of linkages as a gradient, with more a2,6 linked sialic acids present in the upper airway transitioning to more a2,3 linked sialic acids in the lower airway³. Some avian viruses can only replicate effectively in cells that express a2,3 linked sialic acids, which in humans is limited to the lower respiratory tract, which may serve as barrier to interspecies transmission and require that successful zoonosis is contingent upon the ability of the virus to bind a2,6 linked sialic acids, making this a marker of pandemic potential³. However, this is complicated by new evidence that non-binding sialic acids can contribute to enhanced binding and infection through hetero-multivalent interactions⁴. Individual hemagglutinin (HA) interactions with sialic acid glycan receptors are low affinity (K_D ~0,5 to 20mM) leading to a low initial binding rate but high avidity is achieved through multivalent interactions with a receptor coated surface⁴.

Recent findings suggest phosphor-glycans are a potential alternative IAV receptor⁷. Additionally, two subtypes of IAV found exclusively in South and Central American bats (H17N10 and H18N11) use MHC class II for entry^7,8.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Several studies have determined a dissociation constant (K_D) for IAV and sialic acid glycan receptors as follows:

Reference	Technique	Binding partner	Measured Kd
Sauter, N. K. et al. Hemagglutinins from two influenza virus variants bind to sialic acid derivatives with millimolar dissociation constants: a 500-MHz proton nuclear magnetic resonance study. Biochemistry 28, 8388–8396 (1989).	500-MHz proton nuclear magnetic resonance (NMR)	X-31BHA virus (H3N2) with a(2,3)-Sialyl- lactose	3.2 mM
Xiong, X., Coombs, P., Martin, S. et al. Receptor binding by a ferret-transmissible H5 avian influenza virus. Nature 497, 392–396 (2013). https://doi.org/10.1038/nature12144	microscale thermophoresis (MST) using recombinant HA trimers and surface biolayer interferometry (BLI) with purified viruses	A/Vietnam/1194/2004 (H5N1) with human and avian receptor	Human: 17mM Avian: 1.1mM
Fei, Y. et al. Characterization of Receptor Binding Profiles of Influenza A Viruses Using An Ellipsometry-Based Label-Free Glycan Microarray Assay Platform. Biomolecules 5, 1480–1498 (2015).	Glycan microarray with a scanning ellipsometry sensor	A/Memphis/1971 (A/Mem71, H3N1), A/Udorn/307/1972 (A/Udorn72, H3N2), and A/Philippines/2/82/X-79 (A/Philips, H3N2) with 24 synthetic glycans (oligosaccharides) including include four β1-4-linked galactosides, three β1-3-linked galactosides, one β-linked galactoside, one α-linked N-acetylgalactosaminide, eight α2-3-linked sialosides, and seven α2-6-linked sialosides	100pM
Vachieri, S. G. et al. Receptor binding by H10 influenza viruses. Nature 511, 475–477 (2014).	Biolayer interferometry	H10 virus to human and avian receptor	Avian: 1.81 ± 0.39 mM Human: 1.39 ± 0.32 mM,

Other studies have characterized this interaction to identify species specificity:

Reference	Technique	Finding
Rogers, G., Paulson, J., Daniels, R. et al. Single amino acid substitutions in influenza haemagglutinin change receptor binding specificity. Nature 304, 76–78 (1983). https://doi.org/10.1038/304076a0	Hemagglutination assay, HAI	Specific mutations at site 226 in HA impact sialic acid linkage binding preference
Rogers GN, Pritchett TJ, Lane JL, Paulson JC. Differential sensitivity of human, avian, and equine influenza A viruses to a glycoprotein inhibitor of infection: selection of receptor specific variants. Virology. 1983 Dec;131(2):394-408. doi: 10.1016/0042-6822(83)90507-x. PMID: 6197808.	Hemagglutination assay, HAI	Human, avian, and equine H3 Influenza A viruses have different abilities to bind sialic acid (human prefer 2,6, animals prefer 2,3).
Childs, R., Palma, A., Wharton, S. et al. Receptor-binding specificity of pandemic influenza A (H1N1) 2009 virus determined by carbohydrate microarray. Nat Biotechnol 27, 797–799 (2009). https://doi.org/10.1038/nbt0909-797	Carbohydrate microarray	Pandemic viruses were able to bind both 2,6 and 2,3 linked sialyl glycans while seasonal viruses only bound 2,6
Matrosovich M, Tuzikov A, Bovin N, Gambaryan A, Klimov A, Castrucci MR, Donatelli I, Kawaoka Y. Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals. J Virol. 2000 Sep;74(18):8502-12. doi: 10.1128/jvi.74.18.8502-8512.2000. PMID: 10954551; PMCID: PMC116362.	Solid- phase receptor binding assay	Alteration of receptor binding efficiency may be a prerequisite for zoonosis
Crusat M, Liu J, Palma AS, Childs RA, Liu Y, Wharton SA, Lin YP, Coombs PJ, Martin SR, Matrosovich M, Chen Z, Stevens DJ, Hien VM, Thanh TT, Nhu le NT, Nguyet LA, Ha do Q, van Doorn HR, Hien TT, Conradt HS, Kiso M, Gamblin SJ, Chai W, Skehel JJ, Hay AJ, Farrar J, de Jong MD, Feizi T. Changes in the hemagglutinin of H5N1 viruses during human infection--influence on receptor binding. Virology. 2013 Dec;447(1-2):326-37. doi: 10.1016/j.virol.2013.08.010. Epub 2013 Sep 17. PMID: 24050651; PMCID: PMC3820038.	Hemagglutination assay, receptor binding assay using sialylglycopolymers, biolayer interferometry analysis, carbohydrate microarray analysis, crystallography	H5N1 infection of human leads to decreased ability to bind 2,3 linked sialic acid

Domain of Applicability

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References

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References:

Paulson, J. and Rogers, G. Receptor determinants of human and animal influenza virus isolates: Differences in recptor specificity of the H3 hemagglutinin based on species of origin. Virology 127:2, 361-373 (1983). https://doi.org/10.1016/0042-6822(83)90150-2
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Shinya, K., Ebina, M., Yamada, S. et al. Influenza virus receptors in the human airway. Nature 440, 435–436 (2006). https://doi.org/10.1038/440435a
Liu, M., Huang, L.Z.X., Smits, A.A. et al. Human-type sialic acid receptors contribute to avian influenza A virus binding and entry by hetero-multivalent interactions. Nat Commun13, 4054 (2022). https://doi.org/10.1038/s41467-022-31840-0
Matrosovich M, Herrler G, Klenk HD. Sialic Acid Receptors of Viruses. Top Curr Chem. 2015;367:1-28. doi: 10.1007/128_2013_466. PMID: 23873408; PMCID: PMC7120183.
Human Protein Atlas proteinatlas.org
Sempere Borau, M and Stertz, S Entry of Influenza A virus into host cells- recent progress and remaining challenges. Current Opinion in Virology. 2021 doi: https://doi.org/10.1016/j.coviro.2021.03.001
Karakus, U., Thamamongood, T., Ciminski, K. et al. MHC class II proteins mediate cross-species entry of bat influenza viruses. Nature 567, 109–112 (2019). https://doi.org/10.1038/s41586-019-0955-3