Host prion protein expression levels impact prion tropism for the spleen
Host prion protein expression levels impact prion tropism for the spleen
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DOI：
10.1371/journal.ppat.1008283
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发表时间：
2020-07-01
期刊：
影响因子：
6.7
通讯作者：
Laude, Hubert
中科院分区：
文献类型：
--
作者：
Beringue, Vincent;Tixador, Philippe;Laude, Hubert
朊病毒是由宿主编码的细胞朊病毒蛋白（PrPC）的异常构象（PrPSc）形成的病原体。PrPSc构象与疾病表型的关系在朊病毒株之间有很大差异。特别是，朊病毒表现出对淋巴组织的应变依赖性向性。朊病毒可以由几个亚株组成。有证据表明，这些亚株可以在单个个体的不同组织（例如脑和脾）中繁殖，为研究朊病毒组织选择性的原因提供了实验范例。以前，我们表明，PrPC表达水平的功能在朊病毒亚型的选择在大脑中。绵羊瘙痒病分离株（称为LAN）的多个行的转基因小鼠在他们的大脑中表达不同水平的绵羊PrPC导致在表型表达的优势羊亚株在小鼠中表达接近生理PrPC水平，而一个次要的亚株复制优先高expresser小鼠。考虑到PrPC的表达水平显着下降，在脾脏相比，大脑，我们询问是否脾PrPC剂量可以驱动朊病毒的选择性。从高表达小鼠的脾脏中的LAN分离物的大队列的传输的结果与复制率依赖于PrPC量相关。有一个突出的脾脏定植的亚株优先复制低expresser小鼠和一个相对无能的亚株与较高的PrPC水平需要在脾脏中繁殖。腹膜内接种后脾脏的早期定植允许淋巴亚株的神经病理学表达。此外，一对亚株变体的适应人类朊病毒的绵羊高表达小鼠，并表现出不同的大脑与脾脏的嗜性，表现出不同的嗜性传输到低表达小鼠，与淋巴亚株定殖的大脑。总体而言，这些数据表明，PrPC的表达水平是在朊病毒lymphotropis.Author摘要朊病毒株之间的朊病毒表型变异的原因仍然知之甚少。特别是，朊病毒在脾脏中以应变依赖的方式复制。这可能导致朊病毒无症状携带者。根据我们以前的观察，剂量的朊病毒前体（PrP）确定朊病毒亚型的选择在大脑中，我们检查是否PrP水平在脾脏可以驱动朊病毒复制在这个组织中，由于低水平的蛋白质。我们观察到具有较高PrP复制需要的朊病毒亚株在脾脏中几乎不复制，而具有低PrP需要的组分有效地复制。此外，其他具有不同脾脏和大脑嗜性的人类共同传播朊病毒在传播给表达低PrP水平的小鼠时表现出不同的嗜性，其中淋巴亚株定植于大脑。因此，PrPC表达水平可能有助于朊病毒对淋巴组织的嗜性。从诊断的角度来看，鉴于朊病毒疾病的朊病毒亚株组成的明显复杂性，这些数据主张对神经组织或液体进行分型，以全面鉴定易感哺乳动物中的循环朊病毒。
Prions are pathogens formed from abnormal conformers (PrPSc) of the host-encoded cellular prion protein (PrPC). PrPSc conformation to disease phenotype relationships extensively vary among prion strains. In particular, prions exhibit a strain-dependent tropism for lymphoid tissues. Prions can be composed of several substrain components. There is evidence that these substrains can propagate in distinct tissues (e.g. brain and spleen) of a single individual, providing an experimental paradigm to study the cause of prion tissue selectivity. Previously, we showed that PrPC expression levels feature in prion substrain selection in the brain. Transmission of sheep scrapie isolates (termed LAN) to multiple lines of transgenic mice expressing varying levels of ovine PrPC in their brains resulted in the phenotypic expression of the dominant sheep substrain in mice expressing near physiological PrPC levels, whereas a minor substrain replicated preferentially on high expresser mice. Considering that PrPC expression levels are markedly decreased in the spleen compared to the brain, we interrogate whether spleen PrPC dosage could drive prion selectivity. The outcome of the transmission of a large cohort of LAN isolates in the spleen from high expresser mice correlated with the replication rate dependency on PrPC amount. There was a prominent spleen colonization by the substrain preferentially replicating on low expresser mice and a relative incapacity of the substrain with higher-PrPC level need to propagate in the spleen. Early colonization of the spleen after intraperitoneal inoculation allowed neuropathological expression of the lymphoid substrain. In addition, a pair of substrain variants resulting from the adaptation of human prions to ovine high expresser mice, and exhibiting differing brain versus spleen tropism, showed different tropism on transmission to low expresser mice, with the lymphoid substrain colonizing the brain. Overall, these data suggest that PrPC expression levels are instrumental in prion lymphotropism.Author summary The cause of prion phenotype variation among prion strains remains poorly understood. In particular, prions replicate in a strain-dependent manner in the spleen. This can result in prion asymptomatic carriers. Based on our previous observations that dosage of the prion precursor (PrP) determined prion substrain selection in the brain, we examine whether PrP levels in the spleen could drive prion replication in this tissue, due to the low levels of the protein. We observe that the prion substrain with higher PrP need for replication does barely replicate in the spleen, while the component with low PrP need replicates efficiently. In addition, other human co-propagating prions with differing spleen and brain tropism showed different tropism on transmission to mice expressing low PrP levels, with the lymphoid substrain colonizing the brain. PrPC expression levels may thus be instrumental in prion tropism for the lymphoid tissue. From a diagnostic point of view, given the apparent complexity of prion diseases with respect to prion substrain composition, these data advocate to type extraneural tissues or fluids for a comprehensive identification of the circulating prions in susceptible mammals.