Influenza A Virus (IAV) binds sialic acid glycan receptor

GO:0030665

GO clathrin-coated vesicle membrane

PR:000049750

PR influenzavirus hemagglutinin

GO:0012506

GO vesicle membrane

GO:0005102

GO receptor binding

GO:0036010

GO protein localization to endosome

GO:0006898

GO receptor-mediated endocytosis

GO:0061025

GO membrane fusion

WIKI occurrence

Influenza Virus

2021-12-05T12:32:16

WCS_9606

common toxicological species human

WCS_9031

common ecological species chicken

WikiUser_24

Wikiuser:Migration Pig

10090

NCBI mouse

9685

NCBI cat

WCS_9615

common toxicological species dog

9669

NCBI ferret

10036

NCBI Syrian hamster

10141

NCBI guinea pig

9544

NCBI rhesus macaque

Influenza A Virus (IAV) binds sialic acid glycan receptor

IAV binds receptor

Molecular

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 (KD ~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 entry7,8.

Several studies have determined a dissociation constant (KD) for IAV and sialic acid glycan receptors as follows: <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:medium; color:#000000; font-style:normal; font-weight:400; text-align:start; text-decoration:none; white-space:normal; width:671px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:23px; vertical-align:top; width:273px"> Reference </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:23px; vertical-align:top; width:131px"> Technique </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:23px; vertical-align:top; width:164px"> Binding partner </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:23px; vertical-align:top; width:103px"> Measured Kd </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:273px"> 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). </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:131px"> 500-MHz proton nuclear magnetic resonance (NMR) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:164px"> X-31BHA virus (H3N2) with a(2,3)-Sialyl- lactose </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:103px"> 3.2 mM </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:273px"> 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 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:131px"> microscale thermophoresis (MST) using recombinant HA trimers and surface biolayer interferometry (BLI) with purified viruses </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:164px"> A/Vietnam/1194/2004 (H5N1) with human and avian receptor </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:103px"> Human: 17mM   Avian: 1.1mM </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:273px"> 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). </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:131px"> Glycan microarray with a scanning ellipsometry sensor </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:164px"> 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 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:103px"> 100pM </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:273px"> Vachieri, S. G. et al. Receptor binding by H10 influenza viruses. Nature 511, 475–477 (2014). </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:131px"> Biolayer interferometry </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:164px"> H10 virus to human and avian receptor </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:80px; vertical-align:top; width:103px"> Avian: 1.81 ± 0.39 mM   Human: 1.39 ± 0.32 mM, </td> </tr> </tbody> </table>   Other studies have characterized this interaction to identify species specificity:   <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:medium; color:#000000; font-style:normal; font-weight:400; text-align:start; text-decoration:none; white-space:normal"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:253px"> Reference </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:190px"> Technique </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:181px"> Finding </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:253px"> 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 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:190px"> Hemagglutination assay, HAI </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:181px"> Specific mutations at site 226 in HA impact sialic acid linkage binding preference </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:253px"> 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. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:190px"> Hemagglutination assay, HAI </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:181px"> Human, avian, and equine H3 Influenza A viruses have different abilities to bind sialic acid (human prefer 2,6, animals prefer 2,3). </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:253px"> 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 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:190px"> Carbohydrate microarray </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:181px"> Pandemic viruses were able to bind both 2,6 and 2,3 linked sialyl glycans while seasonal viruses only bound 2,6 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:253px"> 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. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:190px"> Solid- phase receptor binding assay </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:181px"> Alteration of receptor binding efficiency may be a prerequisite for zoonosis </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:253px"> 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. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:190px"> Hemagglutination assay, receptor binding assay using sialylglycopolymers, biolayer interferometry analysis, carbohydrate microarray analysis, crystallography </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:181px"> H5N1 infection of human leads to decreased ability to bind 2,3 linked sialic acid </td> </tr> </tbody> </table>

UBERON:0004802

UBERON respiratory tract epithelium

CL:0000066

CL epithelial cell

High Mixed

High

Adult, reproductively mature

High

During development and at adulthood

High High High High Moderate Moderate High High High High

References: <ol> <li>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). <a href="https://doi.org/10.1016/0042-6822(83)90150-2" style="color:#954f72; text-decoration:underline" target="_blank" title="Persistent link using digital object identifier">https://doi.org/10.1016/0042-6822(83)90150-2</a></li> <li>Get this from thesis</li> <li>Shinya, K., Ebina, M., Yamada, S. et al. Influenza virus receptors in the human airway. Nature 440, 435–436 (2006). <a href="https://doi.org/10.1038/440435a" style="color:#954f72; text-decoration:underline">https://doi.org/10.1038/440435a</a></li> <li>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). <a href="https://doi.org/10.1038/s41467-022-31840-0" style="color:#954f72; text-decoration:underline">https://doi.org/10.1038/s41467-022-31840-0</a></li> <li>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.</li> <li>Human Protein Atlas proteinatlas.org</li> <li>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: <a href="https://doi.org/10.1016/j.coviro.2021.03.001" rel="noreferrer noopener" target="_blank" title="Persistent link using digital object identifier">https://doi.org/10.1016/j.coviro.2021.03.001</a></li> <li>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</li> </ol> AOPWiki 2023-07-31T13:37:09

2023-08-02T10:27:29

Influenza A virus (IAV) cell entry

IAV cell entry

Cellular

IAV has two major surface proteins: hemagglutinin (HA) and neuraminidase (NA). HA binds to sialic acid glycans on the host cell surface to facilitate viral entry (1,2). Following this, the virion enters the cell through receptor—mediated endocytosis (usually involving clathrin) or micropinocytosis (1,3,4). The virus is then trafficked to the endosome, where the change in pH activates the M2 ion channel protein of the virus, leading to a conformational change in the HA exposing the fusion peptide and causing subsequent fusion of the viral envelope with the membrane of the vesicle (1). Following fusion, the vRNPs are released into the cytoplasm in a process known as “uncoating” and trafficked to the nucleus (1).

<table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:medium; color:#000000; font-style:normal; font-weight:400; text-align:start; text-decoration:none; white-space:normal"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:208px"> Reference </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:208px"> Technique </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:208px"> Finding </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Matlin, K.S., Reggio, H., Helenius, A. & Simons, K. Infectious entry pathway of influenza-virus in a canine kidney-cell line. J. Cell Biol. 91, 601–613 (1981) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Electron microscopy </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Virus was seen bound to microvilli, in coated pits, coated vesicles, and large smooth-surfaced vacuoles, low pH was required for fusion, suggesting entry by endocytosis </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Rust, M., Lakadamyali, M., Zhang, F. et al. Assembly of endocytic machinery around individual influenza viruses during viral entry. Nat Struct Mol Biol 11, 567–573 (2004). https://doi.org/10.1038/nsmb769 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Real- time fluorescent microscopy </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Clathrin-mediated and clathrin- and caveolin-independent endocytic pathways used in parallel with similar efficiency </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> De Vries, E. et. al., Dissection of the Influenza A Virus Endocytic Routes Reveals Macropinocytosis as an Alternative Entry Pathway. Plos Pathogens (2011). <a href="https://doi.org/10.1371/journal.ppat.1001329" style="color:#954f72; text-decoration:underline">https://doi.org/10.1371/journal.ppat.1001329</a>   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Luciferase reporter assay </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Macropinocytosis is an alternative entry pathway </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Chen, C. and Zhuang, X. Epsin 1 is a cargo- specific adaptor for the clathrin-mediated endocytosis of the influenza virus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Colocalization of immunofluorescence </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> influenza entry via clathrin- mediated pathway   </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Sieczkarski, S. and Whittaker, G. Influenza Virus Can Enter and Infect Cells in the Absence of Clathrin-Mediated Endocytosis </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> Flow cytommetry </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:208px"> IAV cell entry via non-clathrin dependent route </td> </tr> </tbody> </table>

UBERON:0000065

UBERON respiratory tract

CL:0002368

CL respiratory epithelial cell

High Unspecific

Moderate

All life stages

High High

<ol> <li>Dou, D., et. al. Influenza A Virus Cell Entry, Replication, Virion Assembly, and Movement. Front. Immunol. (2018) <a href="https://doi.org/10.3389/fimmu.2018.01581" style="color:#954f72; text-decoration:underline">https://doi.org/10.3389/fimmu.2018.01581</a></li> <li>Sempere Borau, M. and Stertz, S. Entry of influenza A virus into host cells- recent progress and remaining challenges. Current Opinion in Virology (2021) <a href="https://doi.org/10.1016/j.coviro.2021.03.001" style="color:#954f72; text-decoration:underline">https://doi.org/10.1016/j.coviro.2021.03.001</a></li> <li>Matlin, K.S., Reggio, H., Helenius, A. & Simons, K. Infectious entry pathway of influenza-virus in a canine kidney-cell line. J. Cell Biol. 91, 601–613 (1981) <a href="https://doi.org/10.1083/jcb.91.3.601" style="color:#954f72; text-decoration:underline">https://doi.org/10.1083/jcb.91.3.601</a></li> <li>De Vries, E. et. al., Dissection of the Influenza A Virus Endocytic Routes Reveals Macropinocytosis as an Alternative Entry Pathway. Plos Pathogens (2011). <a href="https://doi.org/10.1371/journal.ppat.1001329" style="color:#954f72; text-decoration:underline">https://doi.org/10.1371/journal.ppat.1001329</a></li> </ol> AOPWiki 2023-08-11T12:25:13

2023-08-11T13:03:53

<upstream-id>68a12074-dfdb-40b1-8bb3-0673e848d59e</upstream-id> <downstream-id>0d3fd203-153f-4bea-9af4-467b490730b9</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4313122240> AOPWiki 2023-08-11T13:42:23

2023-08-11T13:42:23

Binding of Influenza A Virus (IAV) to Sialic Acid Glycan Receptor leads to viral infection proliferation

IAV infection proliferation

Cataia Ives

2.5

This AOP was developed as a proof of concept for the utility of AOPs to model pathogenesis and provide a testable framework for mitigating factor (MF) and countermeasure evaluation. This AOP outlines early key events (KE) leading to viral propagation and spread.

This AOP was developed through focused literature searches of peer-reviewed literature and validated in house (data to be published at a later date).

adjacent

Not Specified

High

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

Not Specified

AOPWiki 2023-07-31T13:32:46

2023-09-25T16:27:15