title: Macrophage-mediated optic neuritis induced by retrograde axonal transport of spike gene recombinant mouse hepatitis virus.
abstract: After intracranial inoculation, neurovirulent mouse hepatitis virus (MHV) strains induce acute inflammation, demyelination, and axonal loss in the central nervous system. Prior studies using recombinant MHV strains that differ only in the spike gene, which encodes a glycoprotein involved in virus-host cell attachment, demonstrated that spike mediates anterograde axonal transport of virus to the spinal cord. A demyelinating MHV strain induces optic neuritis, but whether this is due to the retrograde axonal transport of viral particles to the retina or due to traumatic disruption of retinal ganglion cell axons during intracranial inoculation is not known. Using recombinant isogenic MHV strains, we examined the ability of recombinant MHV to induce optic neuritis by retrograde spread from the brain through the optic nerve into the eye after intracranial inoculation. Recombinant demyelinating MHV induced macrophage infiltration of optic nerves, demyelination, and axonal loss, whereas optic neuritis and axonal injury were minimal in mice infected with the nondemyelinating MHV strain that differs in the spike gene. Thus, optic neuritis was dependent on a spike glycoprotein-mediated mechanism of viral antigen transport along retinal ganglion cell axons. These data indicate that MHV spreads by retrograde axonal transport to the eye and that targeting spike protein interactions with axonal transport machinery is a potential therapeutic strategy for central nervous system viral infections and associated diseases.
authors.affiliation: Scheie Eye Institute, University of Pennsylvania, Philadelphia, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Shindler
authors.forename: Dhriti
authors.initials: D
authors.lastname: Chatterjee
authors.forename: Kaushiki
authors.initials: K
authors.lastname: Biswas
authors.forename: Ashish
authors.initials: A
authors.lastname: Goyal
authors.forename: Mahasweta
authors.initials: M
authors.lastname: Dutt
authors.forename: Mayssa
authors.initials: M
authors.lastname: Nassrallah
authors.forename: Reas S
authors.initials: RS
authors.lastname: Khan
authors.forename: Jayasri
authors.initials: J
authors.lastname: Das Sarma
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D001369:Axons / Q000473:pathology / Q000502:physiology; D018352:Coronavirus Infections / Q000150:complications* / Q000235:genetics; D004195:Disease Models, Animal; D008264:Macrophages / Q000502:physiology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D006517:Murine hepatitis virus / Q000235:genetics / Q000472:pathogenicity*; D009902:Optic Neuritis / Q000209:etiology* / Q000473:pathology* / Q000821:virology; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D014764:Viral Proteins