Generation of novel neuroinvasive prions following intravenous challenge
Generation of novel neuroinvasive prions following intravenous challenge
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DOI：
10.1111/bpa.12598
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发表时间：
2018-11-01
期刊：
影响因子：
6.4
通讯作者：
Sigurdson, Christina J.
中科院分区：
文献类型：
--
作者：
Aguilar-Calvo, Patricia;Bett, Cyrus;Sigurdson, Christina J.
朊病毒通常通过外周神经扩散到中枢神经系统（CNS）。然而，朊病毒构象不同的能力，穿透中枢神经系统，某些纤维状朊病毒复制持续在淋巴组织没有中枢神经系统的进入，导致慢性沉默载体。在英国，变异型克雅氏（vCJD）朊病毒的亚临床携带者估计为1：2000，vCJD朊病毒通过输血传播，然而，神经侵入的循环朊病毒构象尚不清楚。在这里，我们调查朊病毒构象如何影响输入的朊病毒的脑进入小鼠静脉内挑战亚纤维和纤维株。我们发现，大多数菌株渗透到大脑，并导致终端疾病，然而，纤维状朊病毒表现出减少中枢神经系统进入应变依赖性的方式。引人注目的是，高度纤维化的mCWD朊病毒株在脾脏中复制，并在大脑中作为一种新的菌株出现，表明一种新的神经侵袭性朊病毒已从以前的非神经侵袭性菌株中产生。新菌株显示出改变的斑块形态、脑靶向区域和生化特性，并且这些特性在脑内传代后得以保持。朊病毒感染的脾脏的脑内通道重新产生了新的菌株。脾脏朊病毒类似的新菌株的生物化学和脑内通过朊病毒感染的脾脏重新创建的新菌株，共同表明脾脏朊病毒复制作为一个潜在的来源。两者合计，这些结果表明，静脉内暴露于朊病毒污染的血液或血液制品可能会产生新的神经侵袭性朊病毒构象和疾病表型，可能产生的朊病毒复制在非神经组织或构象选择。
Prions typically spread into the central nervous system (CNS), likely via peripheral nerves. Yet prion conformers differ in their capacity to penetrate the CNS; certain fibrillar prions replicate persistently in lymphoid tissues with no CNS entry, leading to chronic silent carriers. Subclinical carriers of variant Creutzfeldt-Jakob (vCJD) prions in the United Kingdom have been estimated at 1:2000, and vCJD prions have been transmitted through blood transfusion, however, the circulating prion conformers that neuroinvade remain unclear. Here we investigate how prion conformation impacts brain entry of transfused prions by challenging mice intravenously to subfibrillar and fibrillar strains. We show that most strains infiltrated the brain and caused terminal disease, however, the fibrillar prions showed reduced CNS entry in a strain-dependent manner. Strikingly, the highly fibrillar mCWD prion strain replicated in the spleen and emerged in the brain as a novel strain, indicating that a new neuroinvasive prion had been generated from a previously non-neuroinvasive strain. The new strain showed altered plaque morphology, brain regions targeted and biochemical properties and these properties were maintained upon intracerebral passage. Intracerebral passage of prion-infected spleen re-created the new strain. Splenic prions resembled the new strain biochemically and intracerebral passage of prion-infected spleen re-created the new strain, collectively suggesting splenic prion replication as a potential source. Taken together, these results indicate that intravenous exposure to prion-contaminated blood or blood products may generate novel neuroinvasive prion conformers and disease phenotypes, potentially arising from prion replication in non-neural tissues or from conformer selection.