Tracking and clarifying differential traits of classical- and atypical L-type bovine spongiform encephalopathy prions after transmission from cattle to cynomolgus monkeys
Tracking and clarifying differential traits of classical- and atypical L-type bovine spongiform encephalopathy prions after transmission from cattle to cynomolgus monkeys
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DOI：
10.1371/journal.pone.0216807
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发表时间：
2019-05-16
期刊：
影响因子：
3.7
通讯作者：
Ono, Fumiko
中科院分区：
文献类型：
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作者：
Hagiwara, Ken'ichi;Sato, Yuko;Ono, Fumiko
经典的(C-)和非典型的L型牛海绵状脑病(BSE)蛋白在牛脑中引起不同的病理表型，并且每种蛋白的疾病相关形式(PrPSc)具有不同的生化特征。牛C-疯牛病病毒是变异的克雅氏病的病原体。到目前为止，还没有人感染L疯牛病病毒的报道，但它们可以通过实验从奶牛传播给食蟹猴(猕猴)，这是一种非人类灵长类动物模型。当传播给猴子时，C-和L-疯牛病病毒在大脑中诱导不同的病理表型。然而，当从感染的脑中分离出这两种蛋白(PrPSc)时，它们具有相似的生化特征(即，凝胶迁移率、糖形式和对蛋白酶K的抗性)。这些相似性表明，L-疯牛病病毒在猴子体内繁殖时，其毒力可能会改变为C-疯牛病病毒。为了阐明这种可能性，我们使用近亲交配的小鼠进行了生物检测。在猴子体内有或没有繁殖的C-BSE蛋白对小鼠都是致病的，在小鼠的二次传代中表现出类似的潜伏期。相比之下，无论在猴子体内繁殖或不在猴子中繁殖，L-疯牛病病毒都不会在小鼠中引起疾病，这表明在这个灵长类动物模型中，L-疯牛病病毒的致病作用并不收敛于C-疯牛病病毒类型。这些结果表明，虽然在食蟹猴体内传播的C-和L-疯牛病病毒具有相似的PrPSc生化特征，并由猴的氨基酸序列组成，但这两种病毒保持了PrPSc菌株特有的构象，在这种构象中，它们编码并保留了独特的致病特性。
Classical-(C-) and atypical L-type bovine spongiform encephalopathy (BSE) prions cause different pathological phenotypes in cattle brains, and the disease-associated forms of each prion protein (PrPSc) has a dissimilar biochemical signature. Bovine C-BSE prions are the causative agent of variant Creutzfeldt-Jakob disease. To date, human infection with L-BSE prions has not been reported, but they can be transmitted experimentally from cows to cynomolgus monkeys (Macaca fascicularis), a non-human primate model. When transmitted to monkeys, C-and L-BSE prions induce different pathological phenotypes in the brain. However, when isolated from infected brains, the two prion proteins (PrPSc) have similar biochemical signatures (i.e., electrophoretic mobility, glycoforms, and resistance to proteinase K). Such similarities suggest the possibility that L-BSE prions alter their virulence to that of C-BSE prions during propagation in monkeys. To clarify this possibility, we conducted bioassays using inbred mice. C-BSE prions with or without propagation in monkeys were pathogenic to mice, and exhibited comparable incubation periods in secondary passage in mice. By contrast, L-BSE prions, either with or without propagation in monkeys, did not cause the disease in mice, indicating that the pathogenicity of L-BSE prions does not converge towards a C-BSE prion type in this primate model. These results suggest that, although C-and L-BSE prions propagated in cynomolgus monkeys exhibit similar biochemical PrPSc signatures and consist of the monkey amino acid sequence, the two prions maintain strain-specific conformations of PrPSc in which they encipher and retain unique pathogenic traits.