A Single-Amino-Acid Substitution in Herpes Simplex Virus 1 Envelope Glycoprotein B at a Site Required for Binding to the Paired Immunoglobulin-Like Type 2 Receptor α (PILRα) Abrogates PILRα-Dependent Viral Entry and Reduces Pathogenesis
| Autor: | Tomomi Morimoto, Jun Arii, Jing Wang, Tadahiro Suenaga, Yasushi Kawaguchi, Hisashi Arase, Hiroomi Akashi |
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| Rok vydání: | 2010 |
| Předmět: |
Glycosylation
viruses Immunology Herpesvirus 1 Human Biology Virus Replication medicine.disease_cause Membrane Fusion Microbiology Virus Cell Line Mice chemistry.chemical_compound Viral Envelope Proteins Viral entry Virology medicine Animals Humans Receptors Immunologic DNA Primers chemistry.chemical_classification Mice Inbred ICR Binding Sites Base Sequence Virulence Heparan sulfate Virus Internalization Molecular biology Herpesvirus glycoprotein B Recombinant Proteins Virus-Cell Interactions Herpes simplex virus Amino Acid Substitution chemistry Viral replication Cell culture Insect Science Host-Pathogen Interactions Female Mutant Proteins Glycoprotein |
| Zdroj: | Journal of Virology. 84:10773-10783 |
| ISSN: | 1098-5514 0022-538X |
| Popis: | Paired immunoglobulin-like type 2 receptor α (PILRα) is a herpes simplex virus 1 (HSV-1) entry receptor that associates with O-glycans on HSV-1 envelope glycoprotein B (gB). Two threonine residues (Thr-53 and Thr-480) in gB, which are required for the addition of the principal gB O-glycans, are essential for binding to soluble PILRα. However, the role of the two threonines in PILRα-dependent viral entry remains to be elucidated. Therefore, we constructed a recombinant HSV-1 carrying an alanine replacement of gB Thr-53 alone (gB-T53A) or of both gB Thr-53 and Thr-480 (gB-T53/480A) and demonstrated that these mutations abrogated viral entry in CHO cells expressing PILRα. In contrast, the mutations had no effect on viral entry in CHO cells expressing known host cell receptors for HSV-1 gD, viral entry in HL60 cells expressing myelin-associated glycoprotein (MAG) (another HSV-1 gB receptor), viral attachment to heparan sulfate, and viral replication in PILRα-negative cells. These results support the hypothesis that gB Thr-53 and Thr-480 as well as gB O-glycosylation, probably at these sites, are critical for PILRα-dependent viral entry. Interestingly, following corneal inoculation in mice, the gB-T53A and gB-T53/480A mutations significantly reduced viral replication in the cornea, the development of herpes stroma keratitis, and neuroinvasiveness. The abilities of HSV-1 to enter cells in a PILRα-dependent manner and to acquire specific carbohydrates on gB are therefore linked to an increase in viral replication and virulence in the experimental murine model. |
| Databáze: | OpenAIRE |
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