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Comparative Study
. 2005 Aug 9;102(32):11462-7.
doi: 10.1073/pnas.0503230102. Epub 2005 Jul 29.

Herpes keratitis in the absence of anterograde transport of virus from sensory ganglia to the cornea

Katarina Polcicova  1 , Partha Sarathi Biswas, Kaustuv Banerjee, Todd W Wisner, Barry T Rouse, David C Johnson
Affiliations
Comparative Study

Herpes keratitis in the absence of anterograde transport of virus from sensory ganglia to the cornea

Katarina Polcicova et al. Proc Natl Acad Sci U S A. .

Abstract

Herpes stromal keratitis is an immunopathologic disease in the corneal stroma leading to scarring, opacity, and blindness, and it is an important problem in common corneal surgeries. Paradoxically, virus antigens are largely focused in the epithelial layer of the cornea and not in the stromal layer, and viral antigens are eliminated before stromal inflammation develops. It is not clear what drives inflammation, whether viral antigens are necessary, or how viral antigens reach the stroma. It has been proposed that herpes simplex virus (HSV) travels from the corneal epithelium to sensory ganglia then returns to the stroma to cause disease. However, there is also evidence of HSV DNA and infectious virus persistent in corneas, and HSV can be transmitted to transplant recipients. To determine whether HSV resident in the cornea could cause herpes stromal keratitis, we constructed an HSV US9- mutant that had diminished capacity to move in neuronal axons. US9- HSV replicated and spread normally in the mouse corneal epithelium and to the trigeminal ganglia. However, US9- HSV was unable to return from ganglia to the cornea and failed to cause periocular skin disease, which requires zosteriform spread from neurons. Nevertheless, US9- HSV caused keratitis. Therefore, herpes keratitis can occur without anterograde transport from ganglia to the cornea, probably mediated by virus persistent in the cornea.

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Figures

Fig. 1.
Fig. 1.
HSV transport between the cornea and ganglia and construction of an HSV US9- mutant (US9- HSV). (A) Cartoon depicting HSV infection spread from the cornea epithelium to the trigeminal (TG) ganglia, followed by anterograde spread to the corneal stroma. Sensory neurons possess both retrograde and anterograde modes of transport; however, for simplicity, the neuron projecting to the epithelium is shown only with retrograde transport. (B) The HSV-1 genome, including US8, US9, and US10 genes, with the US9 gene replaced with GFP sequences. (C) Western blot showing the loss of US9 in US9- HSV-infected cells. gD is a second HSV membrane protein.
Fig. 2.
Fig. 2.
US9- HSV spreads normally in epithelial cells and in mouse cornea. (A) Cultured ARPE-19 epithelial cells were infected with WT, US9-, US9-R, or gE- HSV for 48 h, and then the cells were fixed and stained with rabbit anti-HSV antibodies and secondary fluorescent antibodies. (B) Mice were infected with HSV by corneal scarification; corneas were removed after 2 days and stained by using rabbit anti-HSV antibodies and secondary fluorescent antibodies. (White bar, 100 μm.)
Fig. 3.
Fig. 3.
US9- HSV spreads in neuronal axons in a retrograde but not in an anterograde direction. (A) Groups of five mice were infected with HSV (5 × 105 pfu) by corneal scarification. Corneas and TG ganglia were removed at day 4, homogenized, and pooled within each group, and infectious HSV was assayed by plaque titration. (B) Spread of HSV from the retina to optic centers of the brain was assessed by injecting each virus (2 × 105 pfu) into the vitreous body of the eye. After 5 days, brain sections were stained for viral antigens as in Fig. 2B. SC, superior colliculus; LGN, lateral geniculate nucleus; SCN, suprachiasmatic nucleus. (C) Mice were infected with HSV (3 × 105 pfu) by scarification of the snout. TG ganglia and corneas were removed after 5 days, and infectious HSV was measured in plaque assays.
Fig. 4.
Fig. 4.
US9- HSV causes HSK. Mice were infected with 5 × 104 pfu of WT, US9-, or US9-R HSV-1 by corneal scarification. Photomicrographs were taken of representative corneas after 15 days.
Fig. 5.
Fig. 5.
HSK and periocular skin disease in mice infected with US9- HSV. (A) Mice infected with 5 × 104 pfu of WT HSV-1, US9-, or US9-R by corneal scarification were scored for HSK: 0, normal cornea; 1, mild haze; 2, moderate haze, iris visible; 3, severe haze, iris not visible; 4, severe haze, corneal ulcer; and 5, corneal rupture, after 15 days. (B) HSK scores recorded after various times of infection as in A,in groups of 15 mice. (C) Mice infected with 5 × 103 pfu of each virus and scored as in A.(D) Groups of 15 mice were infected with 5 × 104 pfu of each virus as in A and scored for periocular skin disease: 0, no lesions; 1, minimal eyelid swelling; 2, moderate eyelid swelling accompanied by crusty ocular discharge; 3, severe eyelid swelling and moderate hair loss in periocular skin; and 4, severe swelling with eyes crusted shut, severe periocular hair loss, and skin lesions. The mean disease scores and SDs are shown.
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