• The Role of Tumor Necrosis Factor Alpha (TNF-a) In the Eyes and Brain of HSV-1 Infected Euthymic BALB/C Mice

      Fields, Mark A; Department of Biochemistry and Molecular Biology (2007-12)
      After uniocular anterior chamber (AC) inoculation of HSV-1, virus and TNFalpha (TNF-a) are detected in the eyes and brain o f HSV-1 infected euthymic BALB/c mice. The overall goal o f this study was to investigate the role o f TN F-a in the eyes and brain o f HSV-1 infected BALB/c mice. Mice were treated with thalidomide for TN F-a 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 o f injection was increased. In macrophage depleted mice, both SCN were infected at day 6 p.i. and the titer o f virus in the SCN o f these mice was increased at day 6 and 7 p.i. compared with controls. The titer o f virus in the contralateral (uninoculated) eye o f macrophage depleted mice was increased at day 7 p.i. The results o f these studies suggest that TN F-a plays a role in limiting virus replication in the SCN o f euthymic BALB/c mice and that one source of TN F-a is macrophages. In order to further investigate the role of TNF-a, a recombinant o f HSV-1 (KOS77VF) was constructed that produces TNF-a constitutively. Euthymic BALB/c mice were injected in one anterior chamber with the TNF-a 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 o f KOSTNF -infected mice, TN F-a expression was increased and there were more viral antigen positive cells and immune inflammatory cells. There was earlier microscopic evidence o f retinal infection and destruction in these mice. In addition, the titer o f virus in the uninjected eye was significantly increased in KOSTiVF-infected mice on day 7 p.i. compared with KOSpCI, KOS6{irescue, or with KOS6/? infected mice. These results suggest that overproduction o f TN F-a by HSV-1 (KOS7WF) facilitates spread o f virus infection in the eye through increased inflammation and TNF-a-mediated damage to retinal cells.