Parainfluenza virus type 3 hemagglutinin-neuraminidase

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Human parainfluenza viruses (HPIVs) are a group of respiratory viruses associated with human respiratory diseases including bronchitis, bronchiolitis, and pneumonia[1][2][3]. Paramyxoviruses, including HPIVs, possess an envelope protein hemagglutinin-neuraminidase (HN) that has receptor-cleaving as well as receptor-binding activity where the two activities reside on the same glycoprotein unlike influenza which carries hemagglutinin and neuraminidase activities as individual glycoproteins. HN is also essential for activating the fusion protein (F) to mediate merger of the viral envelope with the host cell membrane [4][5]. For the parainfluenza viruses as well as other HN-containing paramyxoviruses, this single molecule carries out three different but critical activities at specific points in the process of viral entry. The first step in infection by HPIV is binding to the lung cells’ surface via interaction of the viral receptor-binding molecule with sialic acid-containing receptor molecules on the cell surface [6][7]. Structures of three paramyxovirus HNs have been determined; they are Newcastle Disease virus (NDV), HPIV type 3, and HPIV type 5 (formerly called SV5). Determination of the HN structure of hPIV3 (globular domain) show an enzyme active site very similar to that of influenza neuraminidase and PIV5 HN and this appears to also be a binding site. A second site at the dimer interface has been crystallographically determined only for Newcastle Disease virus (NDV) HN, but a rising number of reports postulate the presence of such a second site for other paramyxoviruses [8][9][10][11][12][13]. Interestingly for NDV HN, functional analysis of the two sites indicated that engagement of the first site activates the second [14][15]. Further studies on the relationship between the sialic acid binding and cleavage activity of wildtype and mutant HPIV HNs are ongoing among CFG PIs. A region next to the transmembrane domain of HN (stalk region) is still elusive to crystal determination, however several studies showed the importance of this domain in fusion promotion [16][17][18][19].

To further emphasize the importance of understanding GBP paradigms, CFG PIs have shown that HPIV3 infection in cultured monolayer cells greatly differs from infection in human airway epithelial (HAE) cell cultures or in animal models [20][21][22][23]. HPIV3 with a single amino acid mutation in the HN glycoprotein with better than wildtype growth in cell culture had a disadvantage in an ex vivo or in vivo system, revealing a gap in our understanding of the biology of these viruses in their natural host [24]. This suggests that even slight variations in receptor types may influence HPIV infectivity. Recently a series of studies using glycoarray analysis started to navigate the complexity of the interaction between these viruses and glycomolecules [25]. The three functions of HN depend upon interaction with glycomolecules, therefore understanding whether glycomolecules are preferentially bound, cleave, or activate the fusion process will unravel the biology of these viruses and will help in developing targeted antivirals.


Contents

CFG Participating Investigators contributing to the understanding of this paradigm

CFG Participating Investigators (PIs) contributing to the understanding of parainfluenza virus type 3 HN include: Gillian Air, Theodore Jardetsky, Matteo Porotto, Charles Russell

Progress toward understanding this GBP paradigm

Carbohydrate ligands

Parainfluenza virus type 3 hemagglutinin-neuraminidase binds sialylated glycans. The sialic acid is linked α2-3 to galactose. The minimal binding motif is a pentasaccharide if there are no modifications, but smaller units bind if there is sulfation or fucosylation, as shown in the figure below [26]
File: PIV3glycans.png

Cellular expression of GBP and ligands

Parainfluenza virus type 3 hemagglutinin-neuraminidase is expressed by HPIV paramyxoviruses that bind to sialic acid-containing receptor molecules on the surface of host lung cells.

Biosynthesis of ligands

The parainfluenza viruses type 3 ligands are typical of complex N-linked glycans. The sialyltransferases that generate the PIV3 receptors are ST3GalIII, ST3GalIV, ST3GalVI along with fucosyl transferases Fuc-TIV and Fuc-TVII that generate Sialyl-Lewis x.

Structure

The crystal structure of a hPIV3 HN has been determined in dimer form [27] and serves as the model for glycan binding and neuraminidase studies.
The subunits are colored green and blue. A molecule of inhibitor 2-deoxy-2,3-dehydro-N-acetyl-neuraminic acid is bound to the active site of each subunit (stick model: C, O and N atoms are gray, red and blue respectively). The figure was made using PyMol (Delano Scientific) from PDB file 1V3D.
file: 1V3D.png

Biological roles of GBP-ligand interaction

hPIV HN plays important roles in several distinct steps associated with viral entry, which causes human respiratory infections. For the parainfluenza viruses as well as other paramyxoviruses that utilize hemagglutinin-neuraminidases, the HN protein carries out three different activities in the process of viral entry and release: (1) The first step in infection by human parainfluenza virus is binding to the lung cell surface via interaction of HN with sialic acid-containing receptor molecules on the cell surface.[6][7] (2) HN is also essential for activating the fusion protein to mediate merger of the viral envelope with the host cell membrane.[4][5] (3) Finally, the neuraminidase activity of HN is required for release of the virus from cells.

CFG resources used in investigations

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for "parainfluenza".

Glycan profiling

Receptors for hPIV3 are located in the human respiratory tract. Glycan profiling of human lung tissue has been carried out by the CFG Core C [1].

Glycogene microarray

hPIV HN is not represented on the CFG microarrays, which only contain probes for mouse and human glycogenes.

Knockout mouse lines

No experiments have been published using glycosyltransferase knockout mice.

Glycan array

There have been many resource requests for glycan array screening of paramyxovirus hemagglutinin-neuraminidase (for example, click here). To see all glycan array results for parainfluenza hemagglutinin-neuraminidase, click here.

Related GBPs

  • Other paramyxovirus HNs: some appear to have one site that carries out both activities; others appear to have separate sites. For glycan array results of other paramyxovirus HNs, click here.
  • Human parainfluenza types 1, 2, 4 and 5
  • Newcastle Disease virus
  • Mumps virus

References

  1. ↑ Moscona, A. 2005. Entry of parainfluenza virus into cells as a target for interrupting childhood respiratory disease. J Clin Invest 115(7):1688-98.
  2. ↑ Sato, M. and P.F. 2008. Current status of vaccines for parainfluenza virus infections. Pediatr Infect Dis J 27(10 Suppl):S123-5.
  3. ↑ Johnstone, J., S.R. Majumdar, J.D. Fox, and T.J. Marrie. 2008. Viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation. Chest 134(6):1141-8.
  4. ↑ 4.0 4.1 Lamb, R. 1993. Paramyxovirus fusion: A hypothesis for changes. Virology 197:1-11.
  5. ↑ 5.0 5.1 Iorio, R.M., V.R. Melanson, and P.J. Mahon. 2009. Glycoprotein interactions in paramyxovirus fusion. Future Virol 4(4):335-351.
  6. ↑ 6.0 6.1 Suzuki, T., A. Portner, R.A. Scroggs, M. Uchikawa, N. Koyama, et al. 2001. Receptor specificities of human respiroviruses. J Virol 75(10):4604-13.
  7. ↑ 7.0 7.1 Moscona, A., M. Porotto, S. Palmer, C. Tai, L. Aschenbrenner, et al. 2010. A Recombinant Sialidase Fusion Protein Effectively Inhibits Human Parainfluenza Viral Infection In Vitro and In Vivo. J Infect Dis.
  8. ↑ Zaitsev, V., M. von Itzstein, D. Groves, M. Kiefel, T. Takimoto, et al. 2004. Second sialic acid binding site in newcastle disease virus hemagglutinin-neuraminidase: implications for fusion. J Virol 78(7):3733-41.
  9. ↑ Lawrence, M.C., N.A. Borg, V.A. Streltsov, P.A. Pilling, V.C. Epa, et al. 2004. Structure of the Haemagglutinin-neuraminidase from Human Parainfluenza Virus Type III. J Mol Biol 335(5):1343-57.
  10. ↑ Yuan, P., T.B. Thompson, B.A. Wurzburg, R.G. Paterson, R.A. Lamb, et al. 2005. Structural studies of the parainfluenza virus 5 hemagglutinin-neuraminidase tetramer in complex with its receptor, sialyllactose. Structure 13(5):803-15.
  11. ↑ Lamb, R.A., R.G. Paterson, and T.S. Jardetzky. 2005. Paramyxovirus membrane fusion: lessons from the F and HN atomic structures. Virology 344(1):30-7.
  12. ↑ Bousse, T. and T. Takimoto. 2006. Mutation at residue 523 creates a second receptor binding site on human parainfluenza virus type 1 hemagglutinin-neuraminidase protein. J Virol 80(18):9009-16.
  13. ↑ Porotto, M., M. Fornabaio, G. Kellogg, and A. Moscona. 2007. A second receptor binding site on the human parainfluenza 3 hemagglutinin-neuraminidase contributes to activation of the fusion mechanism. J Virol 81(7):3216-3228.
  14. ↑ Porotto, M., M. Fornabaio, O. Greengard, M.T. Murrell, G.E. Kellogg, et al. 2006. Paramyxovirus receptor-binding molecules: engagement of one site on the hemagglutinin-neuraminidase protein modulates activity at the second site. J Virol 80(3):1204-13.
  15. ↑ Ryan, C., V. Zaitsev, D.J. Tindal, J.C. Dyason, R.J. Thomson, et al. 2006. Structural analysis of a designed inhibitor complexed with the hemagglutinin-neuraminidase of Newcastle disease virus. Glycoconj J 23(1-2):135-41.
  16. ↑ Melanson, V.R. and R.M. Iorio. 2004. Amino acid substitutions in the F-specific domain in the stalk of the newcastle disease virus HN protein modulate fusion and interfere with its interaction with the F protein. J Virol 78(23):13053-61.
  17. ↑ Melanson, V.R. and R.M. Iorio. 2006. Addition of N-glycans in the stalk of the Newcastle disease virus HN protein blocks its interaction with the F protein and prevents fusion. J Virol 80(2):623-33.
  18. ↑ Porotto, M., M. Murrell, O. Greengard, and A. Moscona. 2003. Triggering of human parainfluenza virus 3 fusion protein(F) by the hemagglutinin-neuraminidase (HN): an HN mutation diminishing the rate of F activation and fusion. J Virol 77(6):3647-3654.
  19. ↑ Bishop, K.A., A.C. Hickey, D. Khetawat, J.R. Patch, K.N. Bossart, et al. 2008. Residues in the stalk domain of the hendra virus g glycoprotein modulate conformational changes associated with receptor binding. J Virol 82(22):11398-409.
  20. ↑ Zhang, L., M.E. Peeples, R.C. Boucher, P.L. Collins, and R.J. Pickles. 2002. Respiratory syncytial virus infection of human airway epithelial cells is polarized, specific to ciliated cells, and without obvious cytopathology. J Virol 76(11):5654-66.
  21. ↑ Mellow, T.E., P.C. Murphy, J.L. Carson, T.L. Noah, L. Zhang, et al. 2004. The effect of respiratory synctial virus on chemokine release by differentiated airway epithelium. Exp Lung Res 30(1):43-57.
  22. ↑ Zhang, L., A. Bukreyev, C.I. Thompson, B. Watson, M.E. Peeples, et al. 2005. Infection of ciliated cells by human parainfluenza virus type 3 in an in vitro model of human airway epithelium. J Virol 79(2):1113-24.
  23. ↑ Thompson, C.I., W.S. Barclay, M.C. Zambon, and R.J. Pickles. 2006. Infection of human airway epithelium by human and avian strains of influenza A virus. J Virol 80(16):8060-8.
  24. ↑ Palermo, L., M. Porotto, C. Yokoyama, S. Palmer, B. Mungall, et al. 2009. Human parainfluenza virus infection of the airway epithelium: the viral hemagglutinin-neuraminidase regulates fusion protein activation and modulates infectivity. J Virol 83(13):6900-6908.
  25. ↑ Amonsen, M., D.F. Smith, R.D. Cummings, and G.M. Air. 2007. Human parainfluenza viruses hPIV1 and hPIV3 bind oligosaccharides with alpha2-3-linked sialic acids that are distinct from those bound by H5 avian influenza virus hemagglutinin. J Virol 81(15):8341-5.
  26. ↑ Amonsen, M., D.F. Smith, R.D. Cummings, and G.M. Air. 2007. Human parainfluenza viruses hPIV1 and hPIV3 bind oligosaccharides with alpha2-3-linked sialic acids that are distinct from those bound by H5 avian influenza virus hemagglutinin. J Virol 81(15):8341-5.
  27. ↑ Lawrence, M.C., N.A. Borg, V.A. Streltsov, P.A. Pilling, V.C. Epa, et al. 2004. Structure of the Haemagglutinin-neuraminidase from Human Parainfluenza Virus Type III. J Mol Biol 335(5):1343-57.

Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page: Gillian Air, James Paulson, Matteo Porotto

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