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M.A. Fields, M. Zheng, P. Wall, S.S. Atherton; Spread of Virus After Anterior Chamber Inoculation of a Recombinant of HSV–1 Expressing Tumor Necrosis Factor Alpha (TNF–) . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3046.
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© ARVO (1962-2015); The Authors (2016-present)
Following uniocular anterior chamber (AC) inoculation of HSV–1, virus spreads to the ipsilateral suprachiasmatic nucleus (SCN) by day 5 p.i. and then to the contralateral optic nerve and retina by day 7 p.i. To determine the role of TNF–α in the uninoculated eye, a recombinant of HSV–1 (KOSTNF) was constructed that produces TNF–α constitutively.
Euthymic BALB/c mice were injected in one anterior chamber with 2 × 104 PFU of the TNF–α recombinant (group 1), with 2 × 104 PFU of a recombinant KOS strain of HSV–1 containing the pCI plasmid DNA alone (group 2), or with the parental virus, HSV–1 KOS6ß, containing the LacZ gene. Mice from each group were sacrificed on days 1–7 p.i. and the uninjected eyes were removed. Light or fluorescence immunohistochemistry was used to identify virus–infected cells in the uninjected eye and to determine the location of leukocytes, immune inflammatory factors and TNF–α in the uninjected eye. The titer of virus in the uninjected eye was determined by plaque assay. Gene expression in the uninjected eye was determined by microarray analysis.
In the uninjected eye of KOSTNF–infected mice, TNF–α expression was increased and there were more viral antigen positive cells, leukocytes, and immune inflammatory factors, such as chemokines and neutrophil gelatinase associated lipocalin (NGAL). 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 9 p.i. compared with KOSpCI, (group 2) or with KOS6ß infected mice (group 3) (1.45 × 104, 1.58 × 103, and 6.31 × 102 PFU, respectively, p<0.05).
These results suggest that overproduction of TNF–α by HSV–1 (KOSTNF) facilitates spread of virus infection in the eye through increased inflammation and TNF–α–mediated damage to retinal cells.
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