Genetic depletion of complement receptors CD21/35 prevents terminal prion disease in a mouse model of chronic wasting disease.
Genetic depletion of complement receptors CD21/35 prevents terminal prion disease in a mouse model of chronic wasting disease.
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DOI：
10.4049/jimmunol.1201579
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发表时间：
2012-11-01
期刊：
影响因子：
--
通讯作者：
Zabel MD
中科院分区：
文献类型：
--
作者：
Michel B;Ferguson A;Johnson T;Bender H;Meyerett-Reid C;Pulford B;von Teichman A;Seelig D;Weis JH;Telling GC;Aguzzi A;Zabel MD
补体系统已被证明促进外周朊病毒的发病机制。缺乏补体受体CD21/35的小鼠在腹腔内感染小鼠适应的痒病朊病毒后部分抵抗终末朊病毒病。慢性消耗性疾病（CWD）是圈养和自由放养的美洲虎种群中出现的一种新出现的朊病毒疾病，与痒病一样，已被证明涉及免疫系统，这可能有助于它们相对容易的水平和环境传播。我们发现，过表达宫颈朊蛋白且易感染CWD的小鼠（Tg(cerPrP)5037小鼠），但缺乏CD21/35表达，在外周感染后完全抵抗临床CWD。CD21/35缺陷Tg5037小鼠在整个疾病过程中表现出脾脏朊病毒积累和复制严重受损，类似于感染小鼠瘙痒病的CD21/35缺陷小鼠PrP小鼠。TgA5037;CD21/35-/-小鼠表现出很少或没有与CWD相关的神经病理和错误折叠的沉积，蛋白酶抗性PrP。CD21/35转运到脂筏并介导对朊病毒感染的强烈生发中心反应，我们认为这为朊病毒积累和复制提供了最佳环境。我们进一步提出了CD21/35在选择与亲本菌株相比可能表现出不同人畜共患潜力的朊病毒菌株中存在的朊病毒准种方面的潜在作用。
The Complement System has been shown to facilitate peripheral prion pathogenesis. Mice lacking Complement receptors CD21/35 partially resist terminal prion disease when infected intraperitoneally with mouse-adapted scrapie prions. Chronic wasting disease (CWD) is an emerging prion disease of captive and free-ranging cervid populations that, like scrapie, has been shown to involve the immune system, which probably contributes to their relatively facile horizontal and environmental transmission. Here we show that mice overexpressing the cervid prion protein and susceptible to CWD (Tg(cerPrP)5037 mice) but lack CD21/35 expression completely resist clinical CWD upon peripheral infection. CD21/35 deficient Tg5037 mice exhibit greatly impaired splenic prion accumulation and replication throughout disease, similar to CD21/35 deficient murine PrP mice infected with mouse scrapie. TgA5037;CD21/35-/- mice exhibited little or no neuropathology and deposition of misfolded, protease-resistant PrP associated with CWD. CD21/35 translocates to lipid rafts and mediates a strong germinal center response to prion infection that we propose provides the optimal environment for prion accumulation and replication. We further propose a potential role for CD21/35 in selecting prion quasi-species present in prion strains that may exhibit differential zoonotic potential compared to the parental strains.
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