Ryman Kate D, White Laura J, Johnston Robert E, Klimstra William B
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, USA.
Viral Immunol. 2002;15(1):53-76. doi: 10.1089/088282402317340233.
Type I interferons (IFN-alpha/beta) rapidly confer resistance to alphavirus infection in macrophages and dendritic cells (DC) as evidenced by the dramatically increased susceptibility of these cells in mice with the IFNAR1 subunit of the IFN-alpha/beta receptor ablated (IFNAR1-/-). Normal adult mice develop only a subclinical Sindbis virus infection, whereas infected IFNAR1-/- mice rapidly succumb to a fatal disease. Here, we investigated the individual and combined contributions of the two best characterized INF-alpha/beta-mediated antiviral pathways to the control of Sindbis virus replication: (1) the coupled 2-5A synthetase/RNase L pathway and (2) the double-stranded RNA-dependent protein kinase (PKR) pathway. Surprisingly, mice deficient in PKR, RNase L, and Mx-1 (triply-deficient [TD]) developed only subclinical infection. Although the permissivity of cells in lymph nodes draining the inoculation site was increased in the absence of PKR/RNase L, systemic dissemination of the virus infection was restricted by an alternative IFN-alpha/beta receptor-dependent mechanism. In vitro, suppression of early virus protein synthesis and virion production in primary bone marrow-derived dendritic cells (BMDC) was largely dependent on the PKR pathway. However, later in infection virion production was reduced even in the absence of PKR/RNase L by an IFN-alpha/beta receptor-dependent mechanism. Priming of BMDC with IFN-alpha/beta or IFN-gamma resulted in dose-dependent restriction of virus replication, largely independent of PKR and/or RNase L expression.
I型干扰素（IFN-α/β）能迅速使巨噬细胞和树突状细胞（DC）对甲病毒感染产生抗性，这一点可通过缺乏IFN-α/β受体的IFNAR1亚基的小鼠（IFNAR1-/-）中这些细胞易感性显著增加得到证明。正常成年小鼠仅发生亚临床辛德毕斯病毒感染，而感染的IFNAR1-/-小鼠会迅速死于致命疾病。在此，我们研究了两种最具特征的IFN-α/β介导的抗病毒途径对辛德毕斯病毒复制控制的单独及联合作用：（1）偶联的2-5A合成酶/RNase L途径和（2）双链RNA依赖性蛋白激酶（PKR）途径。令人惊讶的是，缺乏PKR、RNase L和Mx-1的小鼠（三重缺陷[TD]）仅发生亚临床感染。尽管在没有PKR/RNase L的情况下，接种部位引流淋巴结中的细胞允许性增加，但病毒感染的全身扩散受到另一种IFN-α/β受体依赖性机制的限制。在体外，原代骨髓来源的树突状细胞（BMDC）中早期病毒蛋白合成和病毒粒子产生的抑制很大程度上依赖于PKR途径。然而，在感染后期，即使没有PKR/RNase L，病毒粒子的产生也通过IFN-α/β受体依赖性机制减少。用IFN-α/β或IFN-γ预处理BMDC会导致病毒复制受到剂量依赖性限制，这在很大程度上与PKR和/或RNase L的表达无关。
