Oral Prion Disease Pathogenesis Is Impeded in the Specific Absence of CXCR5-Expressing Dendritic Cells.
Oral Prion Disease Pathogenesis Is Impeded in the Specific Absence of CXCR5-Expressing Dendritic Cells.
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DOI：
10.1128/jvi.00124-17
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发表时间：
2017-05-15
影响因子：
5.4
通讯作者：
Mabbott NA
中科院分区：
文献类型：
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作者：
Bradford BM;Reizis B;Mabbott NA
口服暴露后，某些朊病毒株在小肠Peyer斑块的基质细胞衍生滤泡树突状细胞（FDC）上的早期复制对于疾病向大脑的有效传播至关重要。然而，关于朊病毒最初是如何从肠腔转移到FDC上建立感染的，人们知之甚少。我们之前的数据表明，CD11c+常规树突状细胞等单核吞噬细胞在朊病毒从肠腔进入Peyer's补丁的初始传播中发挥了重要作用。然而，这些细胞是否将口服获得的朊病毒传递给Peyer's斑块内的FDC尚不清楚。趋化因子CXCL13由FDC和滤泡基质细胞表达，并调节表达cxcr5的细胞向含有FDC的B细胞滤泡的归巢。在这里，我们创建了一种新的化合物转基因小鼠，其中CXCR5缺陷特异性地局限于CD11c+细胞。这些小鼠被用来确定表达cxcr5的常规树突状细胞是否在口服暴露后向FDC传播朊病毒。我们的数据显示，在特异性缺乏表达cxcr5的常规树突状细胞的情况下，朊病毒在Peyer斑块和脾脏的FDC上的早期积累受到损害，疾病易感性显著降低。这些数据表明，表达cxcr5的常规树突状细胞在Peyer’s斑块内口服朊病毒向FDC有效传播以建立宿主感染中发挥重要作用。许多天然朊病毒疾病是通过口服受污染的食物或牧草而获得的。一旦朊病毒到达大脑，就会引起广泛的神经变性，最终导致死亡。为了使朊病毒有效地从肠道扩散到大脑，它们首先在肠道Peyer's斑块内的滤泡树突状细胞上复制。朊病毒如何首先传递到滤泡树突状细胞并建立感染尚不清楚。了解这一过程很重要，因为防止朊病毒感染滤泡树突状细胞的治疗方法可以阻止它们扩散到大脑。我们创造的小鼠中，可移动的常规树突状细胞不能向滤泡树突状细胞迁移。在这些小鼠中，朊病毒在滤泡树突状细胞上的早期积累受到损害，口腔朊病毒疾病的易感性降低。这表明朊病毒利用传统的树突状细胞来促进它们向滤泡树突状细胞的初始传递，从而建立宿主感染。
After oral exposure, the early replication of certain prion strains upon stromal cell-derived follicular dendritic cells (FDC) in the Peyer's patches in the small intestine is essential for the efficient spread of disease to the brain. However, little is known of how prions are initially conveyed from the gut lumen to establish infection on FDC. Our previous data suggest that mononuclear phagocytes such as CD11c+ conventional dendritic cells play an important role in the initial propagation of prions from the gut lumen into Peyer's patches. However, whether these cells conveyed orally acquired prions toward FDC within Peyer's patches was not known. The chemokine CXCL13 is expressed by FDC and follicular stromal cells and modulates the homing of CXCR5-expressing cells toward the FDC-containing B cell follicles. Here, novel compound transgenic mice were created in which a CXCR5 deficiency was specifically restricted to CD11c+ cells. These mice were used to determine whether CXCR5-expressing conventional dendritic cells propagate prions toward FDC after oral exposure. Our data show that in the specific absence of CXCR5-expressing conventional dendritic cells the early accumulation of prions upon FDC in Peyer's patches and the spleen was impaired, and disease susceptibility significantly reduced. These data suggest that CXCR5-expressing conventional dendritic cells play an important role in the efficient propagation of orally administered prions toward FDC within Peyer's patches in order to establish host infection. IMPORTANCE Many natural prion diseases are acquired by oral consumption of contaminated food or pasture. Once the prions reach the brain they cause extensive neurodegeneration, which ultimately leads to death. In order for the prions to efficiently spread from the gut to the brain, they first replicate upon follicular dendritic cells within intestinal Peyer's patches. How the prions are first delivered to follicular dendritic cells to establish infection was unknown. Understanding this process is important since treatments which prevent prions from infecting follicular dendritic cells can block their spread to the brain. We created mice in which mobile conventional dendritic cells were unable to migrate toward follicular dendritic cells. In these mice the early accumulation of prions on follicular dendritic cells was impaired and oral prion disease susceptibility was reduced. This suggests that prions exploit conventional dendritic cells to facilitate their initial delivery toward follicular dendritic cells to establish host infection.