The Gut-Associated Lymphoid Tissues in the Small Intestine, Not the Large Intestine, Play a Major Role in Oral Prion Disease Pathogenesis.
The Gut-Associated Lymphoid Tissues in the Small Intestine, Not the Large Intestine, Play a Major Role in Oral Prion Disease Pathogenesis.
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DOI：
10.1128/jvi.01544-15
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发表时间：
2015-09
影响因子：
5.4
通讯作者：
Mabbott NA
中科院分区：
文献类型：
--
作者：
Donaldson DS;Else KJ;Mabbott NA
朊病毒病是一种神经退行性疾病，其特征是朊病毒蛋白在受影响的组织中异常折叠。许多天然朊病毒疾病是通过口服获得的，并且在暴露后，一些朊病毒分离物在肠相关淋巴组织（GALT）内的滤泡树突状细胞（FDC）上的早期复制对于疾病向脑的有效传播（神经侵入）是重要的。大肠GALT活检标本中的朊病毒检测已被用于估计人类和动物疾病的患病率。然而，小肠和大肠GALT对口服朊病毒发病机制的相对贡献尚不清楚。为了解决这个问题，我们创造了只在小肠中缺乏含FDC的GALT的小鼠。我们的数据表明，口服朊病毒疾病的易感性显着降低小鼠缺乏小肠GALT。虽然这些小鼠的大肠中含有FDC的GALT，但这些组织不是朊病毒积聚或神经侵袭的早期部位。我们还确定了大肠内的病理学是否会影响朊病毒的发病机制。在口服朊病毒暴露的时间前后，在大肠中一致感染线虫寄生虫鼠鞭虫并不影响疾病的发病机制。总之，这些数据表明，小肠GALT是口服暴露后朊病毒积聚和神经侵袭的主要早期部位。这对我们理解影响感染风险的因素和疾病的临床前诊断具有重要意义。重要性许多自然朊病毒疾病是通过口服获得的。暴露后，一些朊病毒疾病在肠道相关淋巴组织（GALT）中的积累对于疾病向大脑的有效传播至关重要。然而，GALT在小肠和大肠中对口服朊病毒发病机制的相对贡献尚不清楚。我们发现小肠GALT是朊病毒积累的重要早期部位。此外，一致性感染与大肠蠕虫（蠕虫）周围的时间口服朊病毒暴露并不影响疾病的发病机制。这对于我们理解影响朊病毒感染风险的因素和疾病的临床前诊断非常重要。大肠GALT活检标本中朊病毒的检测已被用于估计人类和动物疾病的患病率。然而，我们的数据表明，使用这些活检标本可能会错过在口腔朊病毒感染的早期阶段的个人，并显着低估了疾病的患病率。
Prion diseases are infectious neurodegenerative disorders characterized by accumulations of abnormally folded cellular prion protein in affected tissues. Many natural prion diseases are acquired orally, and following exposure, the early replication of some prion isolates upon follicular dendritic cells (FDC) within gut-associated lymphoid tissues (GALT) is important for the efficient spread of disease to the brain (neuroinvasion). Prion detection within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, the relative contributions of the small and large intestinal GALT to oral prion pathogenesis were unknown. To address this issue, we created mice that specifically lacked FDC-containing GALT only in the small intestine. Our data show that oral prion disease susceptibility was dramatically reduced in mice lacking small intestinal GALT. Although these mice had FDC-containing GALT throughout their large intestines, these tissues were not early sites of prion accumulation or neuroinvasion. We also determined whether pathology specifically within the large intestine might influence prion pathogenesis. Congruent infection with the nematode parasite Trichuris muris in the large intestine around the time of oral prion exposure did not affect disease pathogenesis. Together, these data demonstrate that the small intestinal GALT are the major early sites of prion accumulation and neuroinvasion after oral exposure. This has important implications for our understanding of the factors that influence the risk of infection and the preclinical diagnosis of disease. IMPORTANCE Many natural prion diseases are acquired orally. After exposure, the accumulation of some prion diseases in the gut-associated lymphoid tissues (GALT) is important for efficient spread of disease to the brain. However, the relative contributions of GALT in the small and large intestines to oral prion pathogenesis were unknown. We show that the small intestinal GALT are the essential early sites of prion accumulation. Furthermore, congruent infection with a large intestinal helminth (worm) around the time of oral prion exposure did not affect disease pathogenesis. This is important for our understanding of the factors that influence the risk of prion infection and the preclinical diagnosis of disease. The detection of prions within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, our data suggest that using these biopsy specimens may miss individuals in the early stages of oral prion infection and significantly underestimate the disease prevalence.