title: Utilization of sialylated glycans as coreceptors enhances the neurovirulence of serotype 3 reovirus.
abstract: Mammalian reoviruses display serotype-specific patterns of tropism and disease in the murine central nervous system (CNS) attributable to polymorphisms in viral attachment protein σ1. While all reovirus serotypes use junctional adhesion molecule-A as a cellular receptor, they differ in their utilization of carbohydrate coreceptors. This observation raises the possibility that carbohydrate binding by σ1 influences reovirus pathology in the CNS. In this study, we sought to define the function of carbohydrate binding in reovirus neuropathogenesis. Newborn mice were inoculated intramuscularly with wild-type strain type 3 Dearing (T3D) and T3D-σ1R202W, a point mutant T3D derivative that does not bind sialic acid (SA). Infected mice were monitored for survival, and viral loads at the sites of primary and secondary replication were quantified. Fewer mice inoculated with the wild-type virus survived in comparison to those inoculated with the mutant virus. The wild-type virus also produced higher titers in the spinal cord and brain at late times postinoculation but lower titers in the liver in comparison to those produced by the mutant virus. In addition, the wild-type virus was more virulent and produced higher titers in the brain than the mutant following intracranial inoculation. These animal infectivity studies suggest that T3D-σ1R202W harbors a defect in neural growth. Concordantly, compared with the wild-type virus, the mutant virus displayed a decreased capacity to infect and replicate in primary cultures of cortical neurons, a property dependent on cell surface SA. These results suggest that SA binding enhances the kinetics of reovirus replication in neural tissues and highlight a functional role for sialylated glycans as reovirus coreceptors in the CNS.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Johnna M
authors.initials: JM
authors.lastname: Frierson
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Pruijssers
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Konopka
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Reiter
authors.forename: Ty W
authors.initials: TW
authors.lastname: Abel
authors.forename: Thilo
authors.initials: T
authors.lastname: Stehle
authors.forename: Terence S
authors.initials: TS
authors.lastname: Dermody
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002490:Central Nervous System / Q000821:virology*; D017931:DNA Primers; D007150:Immunohistochemistry; D012089:Mammalian orthoreovirus 3 / Q000302:isolation & purification / Q000378:metabolism / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011134:Polysaccharides / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D019562:Viral Load; D014774:Virulence; D014779:Virus Replication
chemical_list: D017931:DNA Primers; D011134:Polysaccharides; D011991:Receptors, Virus; D019158:N-Acetylneuraminic Acid