Experimental Verification of a Traceback Phenomenon in Prion Infection
Experimental Verification of a Traceback Phenomenon in Prion Infection
复制标题
DOI：
10.1128/jvi.02387-09
复制
发表时间：
2010-04-01
影响因子：
5.4
通讯作者：
Kitamoto, Tetsuyuki
中科院分区：
文献类型：
--
作者：
Kobayashi, Atsushi;Sakuma, Nobuyuki;Kitamoto, Tetsuyuki
散发性CreutzFeldt-Jakob病(SCJD)的临床病理表型与PrP基因129位密码子的等位基因类型(M或V)和异常PrPSc的凝胶迁移率模式有关。将sCJD普恩病毒传递给具有异源基因的人类PrP基因的小鼠(称为跨序列传递)会导致潜伏期延长。我们以前曾报道过，跨序列传播可以产生一种新的具有独特传播性的病毒株，称为溯源现象。为了从实验上验证sCJD-VV2蛋白的溯源，我们将sCJD-VV2蛋白接种到表达人PrP基因129M/M的小鼠体内。这些129M/M小鼠在长时间的潜伏期后表现出神经病理改变和一种新的PrPSc类型。然后，我们将接种了sCJD-VV2病毒的129M/M小鼠的脑匀浆传代到其他129M/M或129V/V小鼠中。尽管是跨序列传播，但与129M/M小鼠相比，129V/V小鼠对这些普恩病毒高度敏感。接种129M/M小鼠传代的sCJD-VV2蛋白的129V/V小鼠与接种sCJD-VV2蛋白的129V/V小鼠的神经病理学和PrPSc类型相同。此外，除了1型PrPSc特异性抗体外，我们还首次产生了2型PrPSc特异性抗体，并发现PrPSc亚群的剧烈变化是追溯现象的基础。在这里，我们报告的第一个直接证据的追溯性普恩病毒感染。
The clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD) correlate with the allelo-types (M or V) of the polymorphic codon 129 of the human prion protein (PrP) gene and the electrophoretic mobility patterns of abnormal prion protein (PrPSc). Transmission of sCJD prions to mice expressing human PrP with a heterologous genotype (referred to as cross-sequence transmission) results in prolonged incubation periods. We previously reported that cross-sequence transmission can generate a new prion strain with unique transmissibility, designated a traceback phenomenon. To verify experimentally the traceback of sCJD-VV2 prions, we inoculated sCJD-VV2 prions into mice expressing human PrP with the 129M/M genotype. These 129M/M mice showed altered neuropathology and a novel PrPSc type after a long incubation period. We then passaged the brain homogenate from the 129M/M mouse inoculated with sCJD-VV2 prions into other 129M/M or 129V/V mice. Despite cross-sequence transmission, 129V/V mice were highly susceptible to these prions compared to the 129M/M mice. The neuropathology and PrPSc type of the 129V/V mice inoculated with the 129M/M mouse-passaged sCJD-VV2 prions were identical to those of the 129V/V mice inoculated with sCJD-VV2 prions. Moreover, we generated for the first time a type 2 PrPSc-specific antibody in addition to type 1 PrPSc-specific antibody and discovered that drastic changes in the PrPSc subpopulation underlie the traceback phenomenon. Here, we report the first direct evidence of the traceback in prion infection.