Blättler T, Brandner S, Raeber A J, Klein M A, Voigtländer T, Weissmann C, Aguzzi A
Institute of Neuropathology, Department of Pathology, University of Zürich, Switzerland.
Nature. 1997 Sep 4;389(6646):69-73. doi: 10.1038/37981.
Much available evidence points to a pathological isoform of the prion protein PrP being the infectious agent that causes transmissible spongiform encephalopathies, but the mechanisms controlling the neurotropism of prions are still unclear. We have previously shown that mice that do not express PrP (Prnp[o/o] mice) are resistant to infection by prions, and that if a Prnp(+/+) neurograft is introduced into such animals and these are infected intracerebrally with scrapie, the graft but not the surrounding tissue shows scrapie pathology. Here we show that PrP-expressing neurografts in Prnp(o/o) mice do not develop scrapie histopathology after intraperitoneal or intravenous inoculation with scrapie prions. Prion titres were undetectable in spleens of inoculated Prnp(o/o) mice, but were restored to wild-type levels upon reconstitution of the host lymphohaemopoietic system with PrP-expressing cells. Surprisingly, however, i.p. or i.v. inoculation failed to produce scrapie pathology in the neurografts of 27 out of 28 reconstituted animals, in contrast to intracerebral inoculation. We conclude that transfer of infectivity from the spleen to the central nervous system is crucially dependent on the expression of PrP in a tissue compartment that cannot be reconstituted by bone marrow transfer. Thus the requirement for the normal isoform of PrP in peripheral tissues represents a bottleneck for the spread of prions from peripheral sites to the central nervous system.
大量现有证据表明，朊病毒蛋白PrP的一种病理性异构体是导致传染性海绵状脑病的感染因子，但控制朊病毒嗜神经性的机制仍不清楚。我们之前已经表明，不表达PrP的小鼠（Prnp[o/o]小鼠）对朊病毒感染具有抗性，并且如果将Prnp(+/+)神经移植物引入此类动物，并对其进行脑内羊瘙痒病感染，那么移植物而非周围组织会出现羊瘙痒病病理学变化。在此我们表明，在Prnp(o/o)小鼠中表达PrP的神经移植物在经腹腔或静脉接种羊瘙痒病朊病毒后不会出现羊瘙痒病组织病理学变化。在接种的Prnp(o/o)小鼠的脾脏中检测不到朊病毒滴度，但在用表达PrP的细胞重建宿主淋巴造血系统后，朊病毒滴度恢复到了野生型水平。然而，令人惊讶的是，与脑内接种相比，腹腔内或静脉内接种未能在28只重建动物中的27只的神经移植物中产生羊瘙痒病病理学变化。我们得出结论，传染性从脾脏转移到中枢神经系统关键取决于PrP在一个无法通过骨髓移植重建的组织隔室中的表达。因此，外周组织中对PrP正常异构体的需求代表了朊病毒从外周部位传播到中枢神经系统的一个瓶颈。
