Protective Role of Interferon Regulatory Factor 3-Mediated Signaling against Prion Infection
Protective Role of Interferon Regulatory Factor 3-Mediated Signaling against Prion Infection
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DOI：
10.1128/jvi.06326-11
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发表时间：
2012-05-01
影响因子：
5.4
通讯作者：
Nishida, Noriyuki
中科院分区：
文献类型：
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作者：
Ishibashi, Daisuke;Atarashi, Ryuichiro;Nishida, Noriyuki
由PrP的细胞同种型（PrPC）产生的异常朊蛋白（PrPSc）被认为是传染性海绵状脑病（TSE）的病原体（称为朊病毒）的主要或唯一组分。因为PrP是宿主编码的蛋白质，所以在TSE中不会诱导获得性免疫应答。与此同时，先天免疫系统的激活被认为可以部分阻断TSE的进展;然而，其机制尚不清楚。为了进一步阐明先天免疫系统在朊病毒感染中的作用，我们研究了干扰素调节因子3（IRF3）的功能，IRF3是MyD88独立的I型干扰素（IFN）产生途径的关键转录因子。我们发现，IRF3缺陷小鼠表现出显着更早的发病与三个鼠TSE株，即22 L，FK-1，和鼠牛海绵状脑病（mBSE），腹膜内传播后，比野生型对照。此外，IRF 3的过表达减弱了细胞培养系统中的朊病毒感染，而在用针对IRF 3的小干扰RNA（siRNA）处理的朊病毒感染细胞中，PrPSc增加，这表明IRF 3负调节PrPSc的形成。我们的研究结果提供了新的见解宿主先天免疫系统在朊病毒疾病的发病机制中的作用。
Abnormal prion protein (PrPSc) generated from the cellular isoform of PrP (PrPC) is assumed to be the main or sole component of the pathogen, called prion, of transmissible spongiform encephalopathies (TSE). Because PrP is a host-encoded protein, acquired immune responses are not induced in TSE. Meanwhile, activation of the innate immune system has been suggested to partially block the progression of TSE; however, the mechanism is not well understood. To further elucidate the role of the innate immune system in prion infection, we investigated the function of interferon regulatory factor 3 (IRF3), a key transcription factor of the MyD88-independent type I interferon (IFN) production pathway. We found that IRF3-deficient mice exhibited significantly earlier onset with three murine TSE strains, namely, 22L, FK-1, and murine bovine spongiform encephalopathy (mBSE), following intraperitoneal transmission, than with wild-type controls. Moreover, overexpression of IRF3 attenuated prion infection in the cell culture system, while PrPSc was increased in prion-infected cells treated with small interfering RNAs (siRNAs) against IRF3, suggesting that IRF3 negatively regulates PrPSc formation. Our findings provide new insight into the role of the host innate immune system in the pathogenesis of prion diseases.