Receptor Specificities of Human Respiroviruses

T Suzuki

A Portner

R Scroggs

M Uchikawa

Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105^{; Department of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526,}^{and Central Blood Center, Japanese Red Cross, 4-1-31 Hiroo, Shibuya-ku, Tokyo 150-0012,}^{Japan; and Department of Pathology, The Health Science Center, University of Tennessee, Memphis, Tennessee 38163}³

^{Corresponding author. Mailing address for Takashi Suzuki or Toru Takimoto: Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. Phone: (901) 495-3438. Fax: (901) 523-2622. E-mail:}gro.edujts@otomikat.urot.

Received 2000 Nov 6; Accepted 2001 Feb 13.

Abstract

Through their hemagglutinin-neuraminidase glycoprotein, parainfluenza viruses bind to sialic acid-containing glycoconjugates to initiate infection. Although the virus-receptor interaction is a key factor of infection, the exact nature of the receptors that human parainfluenza viruses recognize has not been determined. We evaluated the abilities of human parainfluenza virus types 1 (hPIV-1) and 3 (hPIV-3) to bind to different types of gangliosides. Both hPIV-1 and hPIV-3 preferentially bound to neolacto-series gangliosides containing a terminal N-acetylneuraminic acid (NeuAc) linked to N-acetyllactosamine (Galβ1-4GlcNAc) by the α2-3 linkage (NeuAcα2-3Galβ1-4GlcNAc). Unlike hPIV-1, hPIV-3 bound to gangliosides with a terminal NeuAc linked to Galβ1-4GlcNAc through an α2-6 linkage (NeuAcα2-6Galβ1-4GlcNAc) or to gangliosides with a different sialic acid, N-glycolylneuraminic acid (NeuGc), linked to Galβ1-4GlcNAc (NeuGcα2-3Galβ1-4GlcNAc). These results indicate that the molecular species of glycoconjugate that hPIV-1 recognizes are more limited than those recognized by hPIV-3. Further analysis using purified gangliosides revealed that the oligosaccharide core structure is also an important element for binding. Gangliosides that contain branched N-acetyllactosaminoglycans in their core structure showed higher avidity than those without them. Agglutination of human, cow, and guinea pig erythrocytes but not equine erythrocytes by hPIV-1 and hPIV-3 correlated well with the presence or the absence of sialic acid-linked branched N-acetyllactosaminoglycans on the cell surface. Finally, NeuAcα2-3I, which bound to both viruses, inhibited virus infection of Lewis lung carcinoma-monkey kidney cells in a dose-dependent manner. We conclude that hPIV-1 and hPIV-3 preferentially recognize oligosaccharides containing branched N-acetyllactosaminoglycans with terminal NeuAcα2-3Gal as receptors and that hPIV-3 also recognizes NeuAcα2-6Gal- or NeuGcα2-3Gal-containing receptors. These findings provide important information that can be used to develop inhibitors that prevent human parainfluenza virus infection.

Abstract

Human parainfluenza viruses are important respiratory tract pathogens. Human parainfluenza virus type 1 (hPIV-1) causes most cases of laryngotracheobronchitis (croup) in children, and human parainfluenza virus type 3 (hPIV-3) is second only to respiratory syncytial virus as a cause of pneumonia and bronchiolitis in infants younger than 6 months old (3, 27). These viruses, which belong to the genus Respirovirus and the family Paramyxoviridae, have two spike glycoproteins, the hemagglutinin-neuraminidase (HN) glycoprotein and the fusion (F) glycoprotein, embedded in the envelope. Parainfluenza virus infection is initiated by the attachment of the HN glycoprotein to sialic acid-containing receptors of target cells (23, 32, 44). It is thought that both sialoglycoproteins (33, 48) and gangliosides (15, 20–23, 39, 45) can act as viral receptors.

The binding specificity of influenza viruses for sialic acid-containing receptors has been well characterized. Influenza A viruses isolated from various animal species recognize different terminal sialic acid sequences (4). Avian influenza A viruses bind to N-acetylneuraminic acid (NeuAc) linked to galactose (Gal) by an α2-3 linkage (NeuAcα2-3Gal) but not by an α2-6 linkage. In contrast, human influenza A viruses display the opposite receptor-binding specificity: they prefer NeuAcα2-6Gal- and not NeuAcα2-3Gal-containing receptors (25). These receptor specificities have been suggested to be one of the factors associated with viral host range and tissue tropism (29).

Among the respiroviruses, only Sendai virus (SV) (murine parainfluenza virus type 1) has been characterized in detail for its receptor determinants in several model systems. SV binds to both ganglio-series (Galβ1-3GalNAc containing) and neolacto-series (Galβ1-4GlcNAc containing) gangliosides with terminal NeuAcα2-3Gal as isoreceptors (15, 20–22, 39, 45). Although the deduced amino acid sequences of the HNs of hPIV-1 and hPIV-3 are similar to that of the HN of SV (e.g., 72 and 62% identical with hPIV-1 and hPIV-3 HNs, respectively) (10, 26), little is known about the receptor specificities of these human parainfluenza viruses. In this study, we evaluated the abilities of hPIV-1 and hPIV-3 to bind to different types of gangliosides. We found that the receptor specificity of respiroviruses varies among subtypes and that the core structure of the sugar chain constitutes an important part of the receptor recognized by hPIV-1 and hPIV-3.

ACKNOWLEDGMENTS

This work was supported by grants AI-38956 and AI-11949 from the National Institute of Allergy and Infectious Diseases, by Cancer Center CORE grant CA-21765 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC).

We thank M. Matrosovich for support of this work and helpful discussions.

ACKNOWLEDGMENTS

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