Zhang Fuquan, Joiner Susan, Linehan Jacqueline M, Pintilii Florin, Nazari Tamsin, Argentina Fabio, Preston Connor, Taema Maged, Cunningham Thomas J, Asante Emmanuel A, Mok Tzehow, Mead Simon, Brandner Sebastian, Collinge John, Wadsworth Jonathan D F
MRC Prion Unit at UCL, Institute of Prion Diseases, University College London, London, United Kingdom.
National Prion Clinic, National Hospital For Neurology and Neurosurgery, University College London NHS Foundation Trust, London, United Kingdom.
PLoS Pathog. 2025 Feb 20;21(2):e1012904. doi: 10.1371/journal.ppat.1012904. eCollection 2025 Feb.
The epizootic prion disease of cattle, bovine spongiform encephalopathy (BSE), caused variant Creutzfeldt-Jakob disease (vCJD) in humans following dietary exposure. Codon 129 polymorphism of the human prion protein gene (PRNP), encoding either methionine (M) or valine (V), dictates the propagation of distinct human prion strains and up to now all but one neuropathologically confirmed vCJD patients have had a 129MM genotype. Concordant with this genetic association, transgenic modelling has established that human PrP 129V is incompatible with the vCJD prion strain and that depending on codon 129 genotype, primary human infection with BSE prions may, in addition to vCJD, result in sporadic CJD-like or novel phenotypes. In 2016 we saw the first neuropathologically confirmed case of vCJD in a patient with a codon 129MV genotype. This patient's neuropathology and molecular strain type were pathognomonic of vCJD but their clinical presentation and neuroradiological features were more typical of sporadic CJD, suggestive of possible co-propagation of another prion strain. Here we report the transmission properties of prions from the brain and lymphoreticular tissues of the 129MV vCJD patient. Primary transmissions into transgenic mice expressing human PrP with different codon 129 genotypes mainly produced neuropathological and molecular phenotypes congruent to those observed in the same lines of mice challenged with prions from 129MM vCJD patient brain, indicative that the vCJD prion strain was the dominant propagating prion strain in the patient's brain. Remarkably however, some transgenic mice challenged with 129MV vCJD patient brain propagated a novel prion strain type which at secondary passage was uniformly lethal in mice of all three PRNP codon 129 genotypes after similar short mean incubation periods. These findings establish that cattle BSE prions can trigger the co-propagation of distinct prion strains in humans.
牛的流行性朊病毒病，即牛海绵状脑病（BSE），在人类因饮食接触后引发了变异型克雅氏病（vCJD）。人类朊病毒蛋白基因（PRNP）的密码子129多态性，编码甲硫氨酸（M）或缬氨酸（V），决定了不同人类朊病毒株的传播，到目前为止，除了一名经神经病理学确诊的vCJD患者外，所有患者都具有129MM基因型。与这种遗传关联相一致，转基因模型已经证实，人类PrP 129V与vCJD朊病毒株不相容，并且根据密码子129基因型，人类原发性感染BSE朊病毒除了可能导致vCJD外，还可能导致散发性克雅氏病样或新的表型。2016年，我们见到了首例经神经病理学确诊的密码子129MV基因型vCJD患者。该患者的神经病理学和分子毒株类型是vCJD的特征性表现，但其临床表现和神经放射学特征更符合散发性克雅氏病，提示可能有另一种朊病毒株共同传播。在此，我们报告来自该129MV vCJD患者脑和淋巴网状组织的朊病毒的传播特性。将其原发性传播到表达不同密码子129基因型人类PrP的转基因小鼠中，主要产生了与用来自129MM vCJD患者脑的朊病毒攻击的同系小鼠中观察到的神经病理学和分子表型一致的结果，表明vCJD朊病毒株是该患者脑中占主导地位的传播性朊病毒株。然而，值得注意的是，一些用129MV vCJD患者脑攻击的转基因小鼠传播了一种新的朊病毒株类型，该毒株在第二代传代时，在所有三种PRNP密码子129基因型的小鼠中，经过相似的短平均潜伏期后均具有致死性。这些发现证实，牛BSE朊病毒可在人类中引发不同朊病毒株的共同传播。
