title: The p14 FAST protein of reptilian reovirus increases vesicular stomatitis virus neuropathogenesis.
abstract: The fusogenic orthoreoviruses express nonstructural fusion-associated small transmembrane (FAST) proteins that induce cell-cell fusion and syncytium formation. It has been speculated that the FAST proteins may serve as virulence factors by promoting virus dissemination and increased or altered cytopathology. To directly test this hypothesis, the gene encoding the p14 FAST protein of reptilian reovirus was inserted into the genome of a heterologous virus that does not naturally form syncytia, vesicular stomatitis virus (VSV). Expression of the p14 FAST protein by the VSV/FAST recombinant gave the virus a highly fusogenic phenotype in cell culture. The growth of this recombinant fusogenic VSV strain was unaltered in vitro but was significantly enhanced in vivo. The VSV/FAST recombinant consistently generated higher titers of virus in the brains of BALB/c mice after intranasal or intravenous infection compared to the parental VSV/green fluorescent protein (GFP) strain that expresses GFP in place of p14. The VSV/FAST recombinant also resulted in an increased incidence of hind-limb paralysis, it infected a larger volume of brain tissue, and it induced more extensive neuropathology, thus leading to a lower maximum tolerable dose than that for the VSV/GFP parental virus. In contrast, an interferon-inducing mutant of VSV expressing p14 was still attenuated, indicating that this interferon-inducing phenotype is dominant to the fusogenic properties conveyed by the FAST protein. Based on this evidence, we conclude that the reovirus p14 FAST protein can function as a bona fide virulence factor.
authors.affiliation: Department of Microbiology and Immunology, Ottawa Health Research Institute, University of Ottawa, Ontario, Canada.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Brown
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Stephenson
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanson
authors.forename: Michael
authors.initials: M
authors.lastname: Kucharczyk
authors.forename: Roy
authors.initials: R
authors.lastname: Duncan
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lichty
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000821:virology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D016254:Mutagenesis, Insertional; D018165:Orthoreovirus / Q000502:physiology*; D010264:Paraplegia; D018353:Rhabdoviridae Infections / Q000473:pathology / Q000821:virology; D018116:Vesiculovirus / Q000235:genetics / Q000472:pathogenicity*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D017361:Viral Nonstructural Proteins; D037521:Virulence Factors