Prion uptake in the gut: identification of the first uptake and replication sites.
Prion uptake in the gut: identification of the first uptake and replication sites.
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DOI：
10.1371/journal.ppat.1002449
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发表时间：
2011-12
期刊：
影响因子：
6.7
通讯作者：
Peters PJ
中科院分区：
文献类型：
--
作者：
Kujala P;Raymond CR;Romeijn M;Godsave SF;van Kasteren SI;Wille H;Prusiner SB;Mabbott NA;Peters PJ
在口服暴露后，朊病毒被认为通过M细胞进入派尔集合淋巴结，并在扩散到神经系统之前首先在滤泡树突细胞（FDC）上积累。朊病毒最初是如何从肠腔中获得的尚不清楚。使用高分辨率免疫荧光和冷冻免疫金电子显微镜，我们报告的贩运朊病毒蛋白（PrP）对派尔氏集结的野生型和PrP缺陷小鼠。PrP在喂食后1天（dpf）在卵泡相关上皮（FAE）的肠上皮细胞的大多泡LAMP 1阳性内体中短暂检测到，并且在M细胞中的水平要低得多。随后，在上皮下圆顶的巨噬细胞的晚期内体隔室中的囊泡上检测到PrP。在7-21 dpf，增加的PrP标记观察到的FDC的质膜上的淋巴集结的生发中心，仅从野生型小鼠，确定FDC作为PrP转换和复制的第一个网站。显示FAE肠细胞衍生的A33蛋白的细胞外囊泡上的PrP的检测暗示了与FAE衍生的囊泡相关的向FDC的运输。到21 dpf，PrP被观察到邻近肌间神经丛内的神经元的质膜上。总之，这些数据确定了一种新的潜在的M细胞的非依赖性机制朊病毒运输，介导的FAE肠细胞，其作用是启动转换和复制后，FDC和随后的肠神经感染。朊病毒疾病是经口传播的，但朊病毒蛋白（PrPSc）的异常折叠亚型如何从胃肠道传播感染神经组织尚不清楚。在这里，我们表明，在目前的文献相比，PrPSc进入派尔集合淋巴结主要是通过专门的肠上皮细胞与低得多的水平通过M细胞贩运。来自均质化PrPSc感染的脑组织的蛋白质跨滤泡相关上皮细胞被转胞吞并递送至巨噬细胞和滤泡树突状细胞，其似乎在感染肠神经之前口服暴露于PrPSc之后充当PrP转化和复制的主要位点。
After oral exposure, prions are thought to enter Peyer's patches via M cells and accumulate first upon follicular dendritic cells (FDCs) before spreading to the nervous system. How prions are actually initially acquired from the gut lumen is not known. Using high-resolution immunofluorescence and cryo-immunogold electron microscopy, we report the trafficking of the prion protein (PrP) toward Peyer's patches of wild-type and PrP-deficient mice. PrP was transiently detectable at 1 day post feeding (dpf) within large multivesicular LAMP1-positive endosomes of enterocytes in the follicle-associated epithelium (FAE) and at much lower levels within M cells. Subsequently, PrP was detected on vesicles in the late endosomal compartments of macrophages in the subepithelial dome. At 7–21 dpf, increased PrP labelling was observed on the plasma membranes of FDCs in germinal centres of Peyer's patches from wild-type mice only, identifying FDCs as the first sites of PrP conversion and replication. Detection of PrP on extracellular vesicles displaying FAE enterocyte-derived A33 protein implied transport towards FDCs in association with FAE-derived vesicles. By 21 dpf, PrP was observed on the plasma membranes of neurons within neighbouring myenteric plexi. Together, these data identify a novel potential M cell-independent mechanism for prion transport, mediated by FAE enterocytes, which acts to initiate conversion and replication upon FDCs and subsequent infection of enteric nerves. Prion diseases are orally transmissible, but how the abnormally folded isoform of the prion protein (PrPSc) transits from the gastrointestinal tract to infect neural tissues is not known. Here we demonstrate that in contrast to the current literature, PrPSc enters Peyer's patches primarily through specialised enterocytes with much lower levels trafficking through M cells. Proteins from homogenized PrPSc infected brain tissue are transcytosed across the follicle-associated epithelium and delivered to macrophages and follicular dendritic cells, which appear to serve as the primary site of PrP conversion and replication following oral exposure to PrPSc before infecting the enteric nerves.
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影响因子：
34.7
作者：
Frost, Bess;Diamond, Marc I.
通讯作者：
Diamond, Marc I.
影响因子：
2.8
作者：
Bradford, Barry M.;Sester, David P.;Mabbott, Neil A.
通讯作者：
Mabbott, Neil A.
影响因子：
82.9
作者：
Brown, KL;Stewart, K;Bruce, ME
通讯作者：
Bruce, ME
影响因子：
6.4
作者：
Foster, Neil;Macpherson, Gordon G.
通讯作者：
Macpherson, Gordon G.
DOI：
10.1073/pnas.0308413101
发表时间：
2004-06-29
影响因子：
11.1
作者：
Fevrier, B;Vilette, D;Raposo, G
通讯作者：
Raposo, G