Intracranial Inoculation Is More Potent Than Intranasal Inoculation for Inducing Optic Neuritis in the Mouse Hepatitis Virus-Induced Model of Multiple Sclerosis

Singh, Manmeet; Khan, Reas S.; Dine, Kimberly; Das Sarma, Jayasri; Shindler, Kenneth S.

Different intra-and extracellular pathways may help facilitate viral transport across olfactory or respiratory epithelial barriers. Endocytosis into olfactory sensory neurons followed by intraneuronal transport to the olfactory bulb, or transcellular transport to the lamina propria via sustentacular cells, have been suggested as potential intracellular pathways (Kristensson and Olsson, 1971; Broadwell and Balin, 1985; Thorne et al., 1995; Doty, 2008; Kristensson, 2011) . Delivery of large molecular weight biological therapies (e.g., stem cells, gene therapy vectors, and large proteins) to the CNS via intranasal administration has been explored as a potential method to treat multiple CNS diseases/disorders including Parkinson's and Alzheimer's diseases, multiple sclerosis, seizures, strokes, and psychiatric disorders (Costantino et al., 2007; Neuwelt et al., 2008; Dhuria et al., 2010) . Spread of smaller peptides through rodent brain following intranasal administration occurs rapidly, with diffuse brain distribution and greatest levels found in olfactory bulbs and trigeminal nerves, just 1 h after treatment. IGF-1 (MW = 7.65 kDa) is one of the most studied proteins using intranasal delivery to the CNS (Thorne et al., 2004) . Even entry of some high molecular weight proteins such as VEGF (MW = 38.2 kDa) to the CNS has been shown following intranasal administration (Yang et al., 2009) . Recently, it has been shown that proteins in a complex biologic therapy, ST266, administered via the intranasal route in rats reached the CNS within 30 min, and ST266 proteins were detected in the vitreous and the optic nerve at markedly higher concentrations than in the brain (Khan et al., 2017) , suggesting a rapid, direct nose-to-optic nerve delivery method for proteins. Whether viruses can follow similar pathways to preferentially spread to optic nerve at low inoculation titers has not been reported, but if such pathways are present, the rapid spread of virus could provide an additional mechanism for immune evasion and therefore promote viral infection at lower inoculation titers.