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Xiaodong Zheng, Robert H. Silverman, Aimin Zhou, Tomoko Goto, Byoung Se Kwon, Herbert E. Kaufman, James M. Hill; Increased Severity of HSV-1 Keratitis and Mortality in Mice Lacking the 2–5A-dependent RNase L Gene. Invest. Ophthalmol. Vis. Sci. 2001;42(1):120-126.
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purpose. The2′,5′-oligoadenylate-dependent RNase L gene functions in the
interferon-inducible RNA decay pathway known as the 2–5A system. The
purpose of this study was to determine whether the absence of this gene
affects the pathogenesis of herpes simplex virus type 1 (HSV-1) ocular
infection in the mouse.
methods. HSV-1 (strain McKrae) was applied bilaterally to unscarified corneas of
RNase L–null mice and congenic controls. To evaluate the severity of
herpetic keratitis, slit lamp examinations (SLE) were performed every
other day for 14 days. To study corneal histology and apoptosis,
HSV-1–inoculated RNase-L-null and congenic control mice, as well as
mock-inoculated mice (apoptosis negative control), were killed at 6 and
18 hours postinoculation (PI). Uninoculated mice that underwent corneal
scarification (apoptosis positive control) were killed 2 hours after
scarification. Eyes were dissected and the corneas processed for light
and transmission electron microscopy and the TUNEL assay.
results. In comparison with the congenic control mice, RNase L–null mice showed
significantly more severe herpetic keratitis (PI day 8, SLE score,
mean ± SEM: 3.27 ± 0.10 vs. 2.34 ± 0.06; P < 0.001) and significantly higher mortality (PI
day 14, 70% vs. 20%; P < 0.001). Few apoptotic
cells were seen in HSV-1–infected RNase L–null mice, although DNA
fragmentation consistent with apoptosis was detected in the corneas of
congenic control mice 6 and 18 hours after HSV-1 inoculation and in
uninfected mice with scarified corneas. Signs of apoptosis were not
present in the mock-infected corneas. Electron microscopic evidence of
keratocytic apoptosis was detected only in the uninfected scarified
corneas and the HSV-1–infected congenic control corneas.
conclusions. The increased severity of ocular disease and increased mortality in the
RNase L–null mice provides evidence, for the first time, that the
2–5A system contributes to protection during ocular herpetic
infection. The reduced frequency of apoptosis in these mice suggests
that one possible mechanism for this protective effect could be the
induction of apoptosis in corneal cells as a means of reducing the
spread of infectious virus.
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