Distinctive roles for 2′,5′-oligoadenylate synthetases and double-stranded RNA-dependent protein kinase R in the in vivo antiviral effect of an adenoviral vector expressing murine IFN-β
Distinctive roles for 2′,5′-oligoadenylate synthetases and double-stranded RNA-dependent protein kinase R in the in vivo antiviral effect of an adenoviral vector expressing murine IFN-β
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DOI：
10.4049/jimmunol.172.9.5638
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发表时间：
2004-05-01
影响因子：
4.4
通讯作者：
Carr, DJJ
中科院分区：
文献类型：
--
作者：
Al-Khatib, K;Williams, BRG;Carr, DJJ
为了评价鼠IFN-β在眼部感染中的抗HSV-1机制，用表达鼠IFN-β的腺病毒载体（AdAFN-beta）转导小鼠。用Ad：IFN-β进行眼部转导导致HSV-1感染后存活率提高。保护作用与1）病毒滴度，2）病毒基因表达，3）IFN-γ水平和4）感染组织中CD 8（+）T淋巴细胞和NK细胞浸润百分比的降低有关。IFN-β的表达导致角膜和三叉神经节（TG）中IFN诱导的抗病毒基因2 '，5'-寡腺苷酸合成酶（OAS 1a）升高，但不导致dsRNA依赖性蛋白激酶R（PKR）升高。基于病毒滴度的测量，与TG中的野生型对照相比，OAS途径的下游效应分子RNA酶L缺陷的小鼠对眼部HSV-1并不更敏感。然而，Ad：IFN-β的功效在RNase L小鼠的眼中暂时丧失。相比之下，PKR缺陷小鼠更容易受到眼部HSV-1感染，并且用Ad：IFN-beta转导后，眼部和TG的抗病毒功效显着减弱。这些结果表明，在不存在外源性IFN的情况下，PKR在控制眼部HSV-1感染中发挥核心作用，而OAS途径似乎对外源性IFN产生反应，有助于以组织限制的方式建立抗病毒环境。
To evaluate the anti-HSV-1 mechanisms of murine IFN-beta in ocular infection, mice were transduced with an adenoviral vector expressing murine IFN-beta (AdAFN-beta). Ocular transduction with Ad:IFN-beta resulted in enhanced survival following infection with HSV-1. The protective effect was associated with a reduction in 1) viral titer, 2) viral gene expression, 3) IFN-gamma levels, and 4) the percentage of CD8(+) T lymphocyte and NK cell infiltration in infected tissue. Expression of IFN-beta resulted in an elevation of the IFN-induced antiviral gene 2',5'-oligoadenylate synthetase (OAS1a) but not dsRNA-dependent protein kinase R (PKR) in the cornea and trigeminal ganglion (TG). Mice deficient in the downstream effector molecule of the OAS pathway, RNase L, were no more sensitive to ocular HSV-1 compared with wild-type controls in the TG based on measurements of viral titer. However, the efficacy of Ad:IFN-beta was transiently lost in the eyes of RNase L mice. By comparison, PKR-deficient mice were more susceptible to ocular HSV-1 infection, and the antiviral efficacy following transduction with Ad:IFN-beta was significantly diminished in the eye and TG. These results suggest that PKR is central in controlling ocular HSV-1 infection in the absence of exogenous IFN, whereas the OAS pathway appears to respond to exogenous IFN, contributing to the establishment of an antiviral environment in a tissue-restricted manner.