Experimental Optic Neuritis Induced by a Demyelinating Strain of Mouse Hepatitis Virus

Abstract

Optic neuritis (ON), an inflammatory demyelinating optic nerve disease, occurs in multiple sclerosis (MS).Pathological mechanisms and potential treatments for ON have been studied via experimental autoimmune MS models. However, evidence suggests that virus-induced inflammation is a likely etiology triggering MS and ON; experimental virus-induced ON models are therefore required. We demonstrate that MHV-A59, a mouse hepatitis virus (MHV) strain that causes brain and spinal cord inflammation and demyelination, induces ON by promoting mixed inflammatory cell infiltration. In contrast, MHV-2, a nondemyelinating MHV strain, does not induce ON. Results reveal a reproducible virus-induced ON model important for the evaluation of novel therapies.Significant neuronal damage, with loss of retinal ganglion cell (RGC) axons that comprise the optic nerve, occurs following inflammatory optic neuritis (ON) and correlates with permanent vision loss (2,6,28). Experimental ON is a useful model to examine mechanisms of neuronal damage in multiple sclerosis (MS) because RGCs can readily be labeled and quantified (23). Rodents immunized with myelin proteins develop experimental autoimmune encephalomyelitis (EAE), a model of MS with inflammation in the brain, spinal cord, and optic nerves (12). Mechanisms of neuronal damage during ON in EAE have been examined but vary between chronic (16, 19) and relapsing (23) EAE models, suggesting that different causes of ON may mediate vision-threatening neuronal damage by distinct mechanisms.MS may be caused by a viral infection triggering an immune response against myelin (1, 26). Studies of virus-mediated models of MS are therefore important for our understanding of disease mechanisms and the development of novel therapies. While virus-induced models of MS exist (15, 26), the incidence of ON has not been characterized.Mouse hepatitis virus (MHV) infection in mice has been used as a model for virus-induced demyelination that mimics many pathological features of MS (9,13,15,27,29). Some neurotropic strains of MHV induce a biphasic neurological disease with acute meningoencephalitis, followed by chronic demyelination (15). Similarly to results for autoimmune mod- els of MS, Dandekar et al. recently demonstrated that axonal damage occurs in mice with MHV-induced demyelination (3).It is not known whether the inflammatory demyelination and axonal loss observed to occur in the MHV-infected mouse brain and spinal cord also affect the optic nerve.In the current study, we inoculated mice with plaque-purified demyelinating strain MHV-A59 (14, 15) and nondemyelinating strain MHV-2 (10). MHV-A59 infects a variety of cell types, including neurons, astrocytes, oligodendrocytes, microglia, and ependymal cells (11,13,15,30), in the central nervous system (CNS) and causes acute encephalitis, meningitis, hepatitis, and chronic demyelination. In contrast, MHV-2, a strain closely related to MHV-A59, has a limited ability to invade the brain and spinal cord, causing meningitis without encephalitis or demyelination ...

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

“…1B); their optic nerves appeared similar to those of mock-infected mice (Fig. 1A) (8). The inability of MHV-2 to induce optic neuritis was expected because MHV-2 does not infect the brain parenchyma and is unable to induce encephalitis (13, 14).…”

“…Experiments were repeated at least 3 times with 3 to 5 mice. Areas of demyelination and inflammation were quantified as previously described (8, 11). All slides were coded and read in a blinded fashion.…”

“…To confirm expected virulence of the strains used, livers from the infected mice were embedded in paraffin, sectioned at 5 μm and stained with H&E (5, 12). The degree of optic nerve inflammation was scored by 2 blinded investigators on a 0- (no inflammation) to 4-(severe inflammation) point scale, as described (8, 11), during the time of peak inflammation (days 5-7 pi). Any amount of inflammation (score of 1 to 4) was considered positive for optic neuritis.…”

Visual abnormalities associated with enhanced optic nerve myelination

“…Normal optic nerve function requires that individual nerve axons be ensheathed by myelin laid down by oligodendrocytes (Waxman and Bangalore, 2004). As a corollary, demyelination is associated with functional and structural abnormalities of the optic nerve (e.g., Tremain & Ikeda, 1983; Bjartmar & Trapp, 2003; Shindler et al, 2006, 2008; Zandian et al, 2009). …”

Steroids Impact on Myelin Repair, Neurogenesis and Visual Pathway in Multiple Sclerosis: Preclinical Perspectives

“…Accumulating evidence on experimental virus-induced ON and transgenic models of the axonal/demyelinating disease and EAE suggest that various etiopathogenic mechanisms can trigger MS-and/or ON-like disease in rodents [34][35][36]. Axonal loss/dysfunction can occur because of a variety of nonviral causes: most notably, neurotoxins and associated downstream or intermediary products, including free radicals/oxidative damage, risk genes, and an array of other predisposing elements such as channel abnormalities/calcium elevations-all of which can lead to destruction of neurons [37][38][39] and contribute to lesions pathogenesis in multiple sclerosis [40][41][42].…”