The role of tumor necrosis factor alpha (TNF-alpha) in the eyes and brain of HSV-1 infected euthymic BALB/c mice

After uniocular anterior chamber (AC) inoculation of HSV-1, virus and TNF-alpha (TNF-alpha) are detected in the eyes and brain of HSV-1 infected euthymic BALB/c mice. The overall goal of this study was to investigate the role of TNF-alpha in the eyes and brain of HSV-1 infected BALB/c mice. Mice were treated with thalidomide for TNF-alpha inhibition or injected with clodronate liposomes to deplete macrophages, and the AC of one eye (ipsilateral) was injected with HSV-1 (KOS). In thalidomide-treated mice, both suprachiasmatic nuclei (SCN) were infected by day 5 p.i. and the titer of virus in the SCN contralateral to the side of injection was increased. In macrophage depleted mice, both SCN were infected at day 6 p.i. and the titer of virus in the SCN of these mice was increased at day 6 and 7 p.i. compared with controls. The titer of virus in the contralateral (uninoculated) eye of macrophage depleted mice was increased at day 7 p.i. The results of these studies suggest that TNF-alpha plays a role in limiting virus replication in the SCN of euthymic BALB/c mice and that one source of TNF-alpha is macrophages. In order to further investigate the role of TNF-alpha, a recombinant of HSV-1 (KOS TNF) was constructed that produces TNF-alpha constitutively. Euthymic BALB/c mice were injected in one anterior chamber with the TNF-alpha recombinant, with a recombinant containing the pCI plasmid, with a recombinant rescue virus, or with the parental virus. Mice from each group were sacrificed on day 1-9 p.i. and the uninjected eyes were removed. In the uninjected eye of KOS TNF-infected mice, TNF-alpha expression was increased and there were more viral antigen positive cells and immune inflammatory cells. There was earlier microscopic evidence of retinal infection and destruction in these mice. In addition, the titer of virus in the uninjected eye was significantly increased in KOSTNF-infected mice on day 7 p.i. compared with KOSpCI, KOS6betarescue, or with KOS 6beta infected mice. These results suggest that overproduction of TNF-alpha by HSV-1 (KOSTNF) facilitates spread of virus infection in the eye through increased inflammation and TNF-alpha-mediated damage to retinal cells.; Index Words: cytokine; brain; eye; herpesvirus; immunomodulator; suprachiasmatic nucleus; TNF-alpha.