Virus-like interference in the latency and prevention of Creutzfeldt-Jakob disease.
Virus-like interference in the latency and prevention of Creutzfeldt-Jakob disease.
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克雅氏病潜伏期和预防中的病毒样干扰。
DOI：
10.1073/pnas.0931192100
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发表时间：
2003
影响因子：
11.1
通讯作者：
Lu,ZhiYun
中科院分区：
文献类型：
--
作者：
Manuelidis,Laura;Lu,ZhiYun
我们之前表明，在小鼠脑内（ic）接种克雅氏病减毒SY株，可以延迟随后用毒性更强的FU株进行ic攻击所引起的临床症状和广泛的神经病理学。使用较低剂量的 SY 和 FU ic，我们在此证明，在没有明显的神经病理学或病理性朊病毒蛋白 (PrP-res) 的情况下，小鼠可以得到很好的保护直到老年。相比之下，仅平行 FU 对照在 1 年前就患上了绝症。为了确定对 SY 反应的因素是否可能是这种效应的一部分，我们评估了 SY 感染后 90 天和 FU 攻击前其他平行小鼠的大脑和血清样本。与这些新鲜 SY 脑匀浆混合后，FU 制剂的感染性显着降低，但与 SY 血清样本混合后却没有显着降低，这表明脑细胞正在制造不稳定的抑制因子，而这些抑制因子是保护性反应的一部分。 SY 感染性太低，无法在这些脑匀浆中检测到。虽然抑制可以通过更高的 FU 剂量来克服，但通过静脉注射观察到对最大剂量 FU 的强大保护作用。接种。由于髓系小胶质细胞具有传染性，并且还可以对外来克雅氏病病原体做出反应，因此，先天免疫很可能是此处显示的深层保护的基础。原则上，应该可以人为地刺激相关的骨髓途径，以更好地预防和/或延迟这些感染的临床和病理后遗症。
We previously showed that intracerebral (ic) inoculation of the attenuated SY strain of Creutzfeld–Jakob disease in mice could delay clinical signs and widespread neuropathology evoked by subsequent ic challenge with the more virulent FU strain. Using lower doses of SY and FU ic, we here demonstrate that mice can be protected well into old age without demonstrable neuropathology or pathologic prion protein (PrP-res). In contrast, parallel FU only controls became terminally diseased 1 year earlier. To determine whether factors elaborated in response to SY might be part of this effect, we evaluated brain and serum samples from additional parallel mice at 90 days after SY infection and just before FU challenge. The infectivity of FU preparations was significantly reduced by mixing with these fresh SY brain homogenates but not by mixing with SY serum samples, suggesting that brain cells were elaborating labile inhibitory factors that were part of the protective response. SY infectivity was too low to be detected in these brain homogenates. Although suppression could be overcome by higher FU doses ic, strong protection against maximal doses of FU was observed by using i.v. inoculations. Because myeloid microglia are infectious and also elaborate many factors in response to the foreign Creutzfeld–Jakob disease agent, it is likely that innate immunity underlies the profound protection shown here. In principle, it should be possible to artificially stimulate relevant myeloid pathways to better prevent and/or delay the clinical and pathological sequelae of these infections.