Glycosylation of PrPC Determines Timing of Neuroinvasion and Targeting in the Brain following Transmissible Spongiform Encephalopathy Infection by a Peripheral Route
Glycosylation of PrPC Determines Timing of Neuroinvasion and Targeting in the Brain following Transmissible Spongiform Encephalopathy Infection by a Peripheral Route
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DOI：
10.1128/jvi.02374-09
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发表时间：
2010-04-01
影响因子：
5.4
通讯作者：
Manson, Jean C.
中科院分区：
文献类型：
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作者：
Cancellotti, Enrico;Bradford, Barry M.;Manson, Jean C.
传染性海绵状脑病（TSE）传染性自然地从周围的进入部位扩散到形成病理病变的中枢神经系统。宿主内的几种途径和细胞已被确定为促进感染过程的重要途径。糖蛋白细胞PrP （PrPC）的表达被认为是中枢神经系统（CNS）传染性复制及其转运到大脑的关键因素，并且已经提出感染因子通过多米诺骨牌效应在细胞间传播。然而，确切地说，这是如何实现的，以及PrP的不同糖型在这些过程中的作用仍有待确定。为了解决这个问题，我们使用了我们独特的基因靶向转基因小鼠模型，表达不同的糖基化形式的PrP。将两种TSE菌株腹腔注射到这些小鼠体内，以评估二糖基化、单糖基化和未糖基化的PrP在感染性向脑传播中的作用。本研究表明宿主PrP的糖基化在决定疾病结局方面具有深远的影响。缺乏二糖基化的PrP可以减缓或预防外周攻击后的疾病发作，这表明完全糖基化的PrP在外周感染因子的复制或其转运到中枢神经系统中发挥重要作用。此外，表达未糖基化PrP的小鼠没有出现临床疾病，表达单糖基化PrP的小鼠与表达二糖基化PrP的小鼠相比，表现出明显不同的神经病理特征。这表明外周接种后脑内的靶向性受到宿主PrP糖基化状态的深刻影响。
Transmissible spongiform encephalopathy (TSE) infectivity naturally spreads from site of entry in the periphery to the central nervous system where pathological lesions are formed. Several routes and cells within the host have been identified as important for facilitating the infectious process. Expression of the glycoprotein cellular PrP (PrPC) is considered a key factor for replication of infectivity in the central nervous system (CNS) and its transport to the brain, and it has been suggested that the infectious agent propagates from cell to cell via a domino-like effect. However, precisely how this is achieved and what involvement the different glycoforms of PrP have in these processes remain to be determined. To address this issue, we have used our unique models of gene-targeted transgenic mice expressing different glycosylated forms of PrP. Two TSE strains were inoculated intraperitoneally into these mice to assess the contribution of diglycosylated, monoglycosylated, and unglycosylated PrP in spreading of infectivity to the brain. This study demonstrates that glycosylation of host PrP has a profound effect in determining the outcome of disease. Lack of diglycosylated PrP slowed or prevented disease onset after peripheral challenge, suggesting an important role for fully glycosylated PrP in either the replication of the infectious agent in the periphery or its transport to the CNS. Moreover, mice expressing unglycosylated PrP did not develop clinical disease, and mice expressing monoglycosylated PrP showed strikingly different neuropathologic features compared to those expressing diglycosylated PrP. This demonstrates that targeting in the brain following peripheral inoculation is profoundly influenced by the glycosylation status of host PrP.