Abstract:
Since prion diseases result from infection and neurodegeneration of the central nervous system (CNS), experimental characterizations of prion strain properties customarily rely on the outcomes of intracerebral challenges. However, natural transmission of certain prions, including those causing chronic wasting disease (CWD) in elk and deer, depends on propagation in peripheral host compartments prior to CNS infection. Using gene-targeted GtE and GtQ mice, which accurately control cellular elk or deer PrP expression, we assessed the impact that peripheral or intracerebral exposures play on CWD prion strain propagation and resulting CNS abnormalities. Whereas oral and intraperitoneal transmissions produced identical neuropathological outcomes in GtE and GtQ mice and preserved the naturally convergent conformations of elk and deer CWD prions, intracerebral transmissions generated CNS prion strains with divergent biochemical properties in GtE and GtQ mice that were changed compared to their native counterparts. While CWD replication kinetics remained constant during iterative peripheral transmissions and brain titers reflected those found in native hosts, serial intracerebral transmissions produced 10-fold higher prion titers and accelerated incubation times. Our demonstration that peripherally and intracerebrally challenged Gt mice develop dissimilar CNS diseases which result from the propagation of distinct CWD prion strains points to the involvement of tissue-specific cofactors during strain selection in different host compartments. Since peripheral transmissions preserved the natural features of elk and deer prions, whereas intracerebral propagation produced divergent strains, our findings illustrate the importance of experimental characterizations using hosts that not only abrogate species barriers but also accurately recapitulate natural transmission routes of native strains.
摘要:
由于朊病毒疾病是由中枢神经系统(CNS)的感染和神经变性引起的,朊病毒应变特性的实验表征通常依赖于脑内挑战的结果。然而,某些病毒的自然传播,包括导致麋鹿和鹿的慢性消耗性疾病(CWD)的疾病,取决于中枢神经系统感染前外周宿主区室的传播。使用基因靶向的GtE和GtQ小鼠,精确控制细胞麋鹿或鹿PrP表达,我们评估了外周或脑内暴露对CWD朊病毒株传播和由此产生的CNS异常的影响.尽管口服和腹膜内传播在GtE和GtQ小鼠中产生相同的神经病理学结果,并保留了麋鹿和鹿CWD病毒的自然趋同构象,脑内传播在GtE和GtQ小鼠中产生了具有不同生化特性的CNS朊病毒菌株,与天然小鼠相比发生了变化。虽然CWD复制动力学在迭代外周传播期间保持恒定,并且脑滴度反映了在天然宿主中发现的那些,连续的脑内传输产生10倍高的朊病毒滴度和加速的孵化时间。我们的证明,外周和脑内攻击的Gt小鼠会发展出不同的CNS疾病,这是由不同的CWDpr病毒菌株的传播引起的,这表明在不同宿主区室的菌株选择过程中,组织特异性辅因子的参与。由于外围传播保留了麋鹿和鹿朊病毒的自然特征,而脑内繁殖产生不同的应变,我们的发现说明了使用宿主进行实验表征的重要性,该宿主不仅可以消除物种障碍,而且可以准确地概括本地菌株的自然传播途径。