Following uniocular anterior chamber inoculation of 1-2 X 104 PFU of the KOS strain of herpes simplex virus type 1 (HSV-1) in euthymic BALB/c mice, acute retinitis develops within 7-8 days in the uninoculated eye while the architecture of the retina of the inoculated eye is preserved. In contrast, anterior chamber inoculation of the same strain and dose of virus in athymic BALB/c mice results in bilateral retinitis. In euthymic mice, the virus leaves the anterior segment via the parasympathetic nerves that supply the iris and ciliary body of the injected eye, and the ipsilateral ciliary ganglion is virus-positive at day 2 p.i. By day 3 p.i. the ipsilateral Edinger-Westpahl nucleus is virus-positive, and from the ipsilateral Edinger-Westphal nucleus, the virus spreads to the ipsilateral suprachiasmatic nucleus by day 5 p.i. From this nucleus, HSV-1 spreads to the contralateral optic nerve and retina at day 7 p.i., coincident with the onset of acute retinitis. The contralateral suprachiasmatic nucleus is virus-positive at day 7 p.i., but virus does not spread from this nucleus and the optic nerve and retina of the inoculated eye do not become virus-positive at this or at any time after inoculation. Since the outcome of anterior chamber inoculation is different in euthymic and athymic mice (unilateral vs. bilateral retinitis), we hypothesize that the cellular immune system interacts with virus within the central nervous system (CNS) to prevent the spread of virus back into the ipsilateral retina in euthymic animals. To address the issue of immunologically medicated control of virus infection and spread in the CNS, we will determine (1) whether the timing of virus spread and/or the sites of virus spread are different in athymic mice than they are in euthymic mice after uniocular anterior chamber inoculation of the KOS strain of HSV-1, (2) where T cells (or their products) interact with virus to prevent retinitis in the injected eyes of euthymic mice, and (30 where intravenously-administered virus-specific immune effector cells protect against retinitis. The ability to limit virus spread at sites in the CNS that are synaptically connected to the optic system is likely to plan an important role in determining the outcome of herpesvirus infections involving neuronal pathways connected to the optic system. Elucidation of where and how protection occurs in the CNS may eventually be useful in design of strategies to limit or prevent herpesvirus- medicated damage in the CNS and/or eyes of human patients.
|Richter, Elizabeth R; Dias, James K; Gilbert 2nd, James E et al. (2009) Distribution of herpes simplex virus type 1 and varicella zoster virus in ganglia of the human head and neck. J Infect Dis 200:1901-6|
|Cathcart, Heather M; Fields, Mark A; Zheng, Mei et al. (2009) Infiltrating cells and IFNgamma production in the injected eye after uniocular anterior chamber inoculation of HSV-1. Invest Ophthalmol Vis Sci 50:2269-75|