Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility.
Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility.
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DOI：
10.1371/journal.ppat.1006075
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发表时间：
2016-12
期刊：
影响因子：
6.7
通讯作者：
Mabbott NA
中科院分区：
文献类型：
--
作者：
Donaldson DS;Sehgal A;Rios D;Williams IR;Mabbott NA
人类和动物的许多自然朊病毒疾病被认为是通过口服受污染的食物或牧草获得的。确定朊病毒建立宿主感染的途径将确定影响口腔朊病毒疾病易感性的重要因素，并制定干预策略。暴露后，朊病毒在小肠派尔集合淋巴结内的早期积累和复制对于疾病向大脑的有效传播至关重要。为了在派伊尔集合淋巴结内复制，朊病毒必须首先穿过肠道上皮。M细胞是覆盖派尔集合淋巴结的上皮内的特化上皮细胞，其转运颗粒抗原和微生物。M细胞发育依赖于RANKL-RANK信号传导，仅在肠上皮中缺失RANK的小鼠完全缺乏M细胞。在这些小鼠中特别缺乏M细胞的情况下，朊病毒在派伊尔集合淋巴结内的积累和疾病向大脑的传播被阻断，这表明M细胞在朊病毒最初转移穿过肠道上皮以建立宿主感染中起关键作用。由于病原体，炎症刺激和衰老可以改变肠道中的M细胞密度，这些因素也可能影响口腔朊病毒疾病的易感性。因此，用RANKL处理小鼠以增强肠道中的M细胞密度。我们发现，在RANKL处理的小鼠中，肠腔中的朊病毒摄取增强，导致生存时间缩短和疾病易感性增加，相当于朊病毒的感染滴度增加10倍。这些数据共同表明，M细胞是口腔朊病毒感染的关键守门人，其在肠道上皮中的密度直接限制或增强疾病易感性。我们的数据表明，改变肠道上皮中M细胞密度的因素可能是影响宿主对口服获得性朊病毒疾病易感性的重要危险因素。朊病毒疾病是影响人类和动物的传染性神经退行性疾病。许多天然朊病毒疾病是通过食用受污染的食物或牧草经口获得的。了解朊病毒如何感染肠道将有助于确定影响疾病易感性的因素，并允许开发新的治疗方法。在口腔感染后，朊病毒首先在肠道淋巴组织（称为派尔集合淋巴结）中积累，然后扩散到大脑，在那里引起神经变性。要做到这一点，朊病毒必须首先穿过肠上皮细胞，这是一层将身体与肠道内容物分开的细胞。M细胞存在于覆盖Peyer集合淋巴结的上皮内，专门用于运输大颗粒和整个细菌穿过肠道上皮。我们发现，M细胞作为口腔朊病毒感染的看门人。在缺乏M细胞的情况下，口腔朊病毒感染被阻断，而M细胞的增加增加朊病毒感染的风险并缩短疾病持续时间。因此，我们的数据表明，诸如病原体感染、炎症和衰老等因素改变了肠道中M细胞的丰度，可能是影响口服获得性朊病毒感染易感性的重要风险因素。
Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer’s patches is essential for the efficient spread of disease to the brain. To replicate within Peyer’s patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer’s patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer’s patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases. Prion diseases are infectious neurodegenerative disorders that affect humans and animals. Many natural prion diseases are orally acquired through consumption of contaminated food or pasture. An understanding of how prions infect the intestine will help identify factors that influence disease susceptibility and allow the development of new treatments. After oral infection prions first accumulate within the lymphoid tissues that line the intestine (known as Peyer’s patches) before they spread to the brain where they cause neurodegeneration. To do this, the prions must first cross the intestinal epithelium, a single layer of cells that separates the body from the gut contents. M cells are found within the epithelium that covers the Peyer’s patches and are specialised to transport large particles and whole bacteria across the gut epithelium. We show that M cells act as the gatekeepers of oral prion infection. In the absence of M cells, oral prion infection is blocked, whereas an increase in M cells increases the risk of prion infection and shortens the disease duration. Therefore, our data demonstrate that factors such as pathogen infection, inflammation and aging, which alter the abundance of M cells in the intestine, may be important risk factors which influence susceptibility to orally-acquired prion infections.
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