Abstract
After uniocular anterior chamber (AC) inoculation of herpes simplex virus type 1 (HSV-1), virus and TNF alpha (TNF-α) are detected in the suprachiasmatic nuclei (SCN). The goal of this study was to investigate the role of TNF-α and macrophages in the brain of HSV-1–infected BALB/c mice. Mice were treated with thalidomide for TNF-α inhibition or injected with clodronate liposomes to deplete macrophages, and the AC of one eye (ipsilateral) was injected with HSV-1 (KOS). The location of HSV-1, macrophages, and TNF-α was determined by fluorescence immunohistochemistry and the titer of virus was determined by plaque assay. Inhibition of TNF-α was determined by reverse transcriptase–polymerase chain reaction (RT-PCR) and depletion of macrophages was assessed by flow cytometry. In thalidomide-treated mice, TNF-α RNA levels were reduced in the SCN. Both SCN were infected by day 5 post inoculation (p.i.) and the titer of virus in the SCN contralateral to the side of injection was increased. The number of splenic macrophages was significantly reduced in clodronate-treated mice compared with controls. 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 days 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. Fewer F4/80+ cells were observed in the SCN of macrophage-depleted mice. The results of these studies suggest that TNF-α plays a role in limiting virus replication in the SCN of euthymic BALB/c mice and that one source of TNF-α is macrophages.
This work was supported by National Institutes of Health grant EY006012 (SSA) and fellowship EY015392 (MAF). The authors gratefully acknowledge the laboratory of Jerry Y. Niederkorn, PhD, University of Texas Southwestern Medical School, Dallas, Texas, for assistance with preparation of liposomes.