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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. 2007;48(13):703.
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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 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. Fluorescence microscopy and hematoxylin and eosin staining were used to identify virus-infected cells in the uninjected eye and to assess the extent of retinal destruction. Leukocyte infiltration and the presence of immune inflammatory factors were evaluated by fluorescence microscopy, flow cytometry, and 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, vascular cell adhesion molecule-1 (VCAM-1), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and neutrophil gelatinase associated lipocalin (NGAL). There was earlier microscopic evidence of retinal infection and destruction in these mice.
These results suggest that overproduction of TNF-α by HSV-1 (KOSTNF) facilitates spread of virus infection in the eye through increased inflammation by immunomodulatory factors and TNF-α-mediated damage to retinal cells.
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