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J Biol Chem ; 295(20): 6926-6935, 2020 05 15.
Article in English | MEDLINE | ID: covidwho-830746

ABSTRACT

Mouse hepatitis virus (MHV; murine coronavirus) causes meningoencephalitis, myelitis, and optic neuritis followed by axonal loss and demyelination. This murine virus is used as a common model to study acute and chronic virus-induced demyelination in the central nervous system. Studies with recombinant MHV strains that differ in the gene encoding the spike protein have demonstrated that the spike has a role in MHV pathogenesis and retrograde axonal transport. Fusion peptides (FPs) in the spike protein play a key role in MHV pathogenesis. In a previous study of the effect of deleting a single proline residue in the FP of a demyelinating MHV strain, we found that two central, consecutive prolines are important for cell-cell fusion and pathogenesis. The dihedral fluctuation of the FP was shown to be repressed whenever two consecutive prolines were present, in contrast to the presence of a single proline in the chain. Using this proline-deleted MHV strain, here we investigated whether intracranial injection of this strain can induce optic neuritis by retrograde axonal transport from the brain to the retina through the optic nerve. We observed that the proline-deleted recombinant MHV strain is restricted to the optic nerve, is unable to translocate to the retina, and causes only minimal demyelination and no neuronal death. We conclude that an intact proline dyad in the FP of the recombinant demyelinating MHV strain plays a crucial role in translocation of the virus through axons and subsequent neurodegeneration.


Subject(s)
Axonal Transport/genetics , Murine hepatitis virus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Animals , Axonal Transport/physiology , Axons/metabolism , Axons/virology , Brain/metabolism , Coronavirus Infections/pathology , Demyelinating Diseases/metabolism , Male , Mice , Mice, Inbred C57BL , Murine hepatitis virus/metabolism , Optic Nerve/metabolism , Optic Nerve/virology , Peptides/metabolism , Proline/metabolism , Sequence Deletion/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins/metabolism
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