Macrophage-Mediated Optic Neuritis Induced by Retrograde Axonal Transport of Spike Gene Recombinant Mouse Hepatitis Virus

Abstract

Following intracranial inoculation, neurovirulent mouse hepatitis virus (MHV) strains induce acute inflammation, demyelination and axonal loss in the CNS. 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 retrograde axonal transport of viral particles to the retina, or if it is 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 following 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 non-demyelinating 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 CNS viral infections and associated diseases.

Microglia Play a Major Role in Direct Viral-Induced Demyelination

“…Together, the data indicate that RSA59 causes meningoencephalitis and demyelination. CNS inflammation consists of a mixed population of inflammatory cells, predominantly macrophages/microglia as well as a smaller population of T lymphocytes as shown previously [17,20,37].…”

SIRT1 Activating compounds reduce oxidative stress mediated neuronal loss in viral induced CNS demyelinating disease

“…Mice infected with the nondemyelinating control strain MHV2 did not show RGC loss compared to non-infected controls. Consistent with RGC loss induced by MHV-A59, a recombinant strain, RSA59, which is isogenic to MHV-A59 except for an EGFP fluorescent marker and which has similar demyelinating properties [32,41] and ability to induce optic neuritis [42], also induced significant RGC loss compared to noninfected control and MHV2 infected mice ( Figure 1).…”

Demyelinating strain of mouse hepatitis virus infection bridging innate and adaptive immune response in the induction of demyelination

“…While A59 and JHM strains have many similarities, JHM is highly neurovirulent and follows different kinetics of accumulation of virus-specific CD4+ and CD8 + T cells. Although activated microglia and macrophages make up the vast majority of early infiltrates, up to day 5 following infection in both strains, T cells are most abundant during peak of the inflammation and thereafter in MHV-JHM, whereas in RSA59 few T cells are present at the peak of inflammation [7][8][9]26]. Thus, it was not clear whether MHV-A59 induced changes in immune response genes would be similar to those found in MHV-JHM infection, yet our current results suggests that there indeed may be similar time courses of innate and adaptive immune responses.…”

“…but reaches its peak by days [25][26][27][28][29][30] (chronic disease phase), when infectious viral particles are below the limit of detection and viral antigen has resolved, but viral RNA persists [2,6,7]. Demyelination and axonal loss depend on the viral hostattachment spike protein, as RSMHV2, a closely related isogenic strain that differs from RSA59 only in the spike gene, can cause meningitis, encephalitis, myelitis and occasional optic neuritis [8] but is unable to cause demyelination or axonal loss. Thus, spike plays a major role in MHV-induced myelin loss and axonal loss, but it is unknown how differences in spike affect gene expression in order to mediate different host tissue responses.…”