Investigating the role of follicular dendritic cells in TSE agent neuroinvasion from lymphoid tissues

传染性海绵状脑病（TSE）是致命的神经退行性疾病。例子包括人类的克雅氏病、牛海绵状脑病、黑尾鹿和麋鹿的慢性消耗病以及绵羊和山羊的瘙痒病。TSE因子的大多数自然传播通过外周暴露发生，例如：摄入（口服）。接种后，TSE因子通常在淋巴组织中的滤泡树突状细胞（FDC）上蓄积，然后感染中枢神经系统（CNS）。FDC对于疾病向CNS的传播（神经侵袭）是关键的，因为在它们不存在的情况下，淋巴组织中的药剂积累和神经侵袭受损。TSE病原体的性质尚不清楚，但宿主细胞朊病毒蛋白（PrPc）的异常同种型（PrPSc）与感染性共同纯化。事实上，在用一些TSE试剂接种后，在FDC上检测到PrPSc。细胞必须表达细胞PrPc以复制TSE因子。虽然在未感染小鼠的FDC上检测到PrPc，但尚不清楚FDC是否表达PrPc并复制TSE因子。消耗FDC的治疗可降低对TSE因子的敏感性。因此，在确定风险和设计针对外周获得性TSE的治疗策略时，彻底了解FDC参与TSE发病机制是重要的。FDC将天然抗原长时间捕获并保留在其表面上。因此，它们参与TSE发病机制可能是捕获从感染细胞释放的TSE试剂并介导其转移到神经元。许多细胞类型分泌富含细胞特异性蛋白的外泌体。FDC可以结合外来体，因此在其表面上展示它们在mRNA水平上不表达的蛋白质。PrPc和PrPSc可以在外泌体中释放，提供了一种机制，通过该机制，FDC可以从其他感染的细胞中获得PrPc和TSE试剂。实验排除了骨髓来源的细胞作为FDC上检测到的PrPc和PrPSc的主要提供者。然而，不能排除非造血细胞（例如：肌肉、内皮、上皮或神经细胞）的参与。我们将使用新的方法来提供FDC生物学及其参与TSE发病机制的重要信息。特别是，我们将解决以下目标：O-1：FDCs表达PrPc或从其他宿主细胞获得它？O-2：FDC是否复制TSE因子，或从其他受感染的宿主细胞获得它们？增加对FDC参与TSE发病机制的理解可能有助于制定治疗策略。

Transmissible spongiform encephalophathies (TSEs) are fatal neurodegenerative diseases. Examples include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) in mule deer and elk, and scrapie in sheep and goats. Most natural transmissions of TSE agents occur by peripheral exposure, eg: ingestion (oral). After inoculation, TSE agents usually accumulate upon follicular dendritic cells (FDCs) in lymphoid tissues before they infect the central nervous system (CNS). FDCs are critical for the spread of disease to the CNS (neuroinvasion) as in their absence agent accumulation in lymphoid tissues and neuroinvasion are impaired. The nature of the TSE agent is not known, but an abnormal isoform (PrPSc) of the host cellular prion protein (PrPc), co-purifies with infectivity. Indeed, PrPSc is detected upon FDCs after inoculation with some TSE agents. Cells must express cellular PrPc to replicate TSE agents. Although PrPc is detected on FDCs in uninfected mice, it is not known if FDCs express PrPc and replicate TSE agents. Treatments that deplete FDCs reduce susceptibility to TSE agents. Thus, a thorough understanding of the involvement of FDCs in TSE pathogenesis is important when determining risk, and designing therapeutic strategies against peripherally-acquired TSEs. FDCs trap and retain native antigens on their surfaces for long durations. Thus their involvement in TSE pathogenesis may be to trap TSE agents released from infected cells and mediate their transfer to neurones. Many cell types secrete exosomes enriched in cell-specific protein. FDCs can bind exosomes, and as a consequence display proteins on their surfaces that they do not express at the mRNA level. PrPc and PrPSc can be released in exosomes, providing a mechanism by which FDCs might acquire PrPc and TSE agents from other infected cells. Experiments have excluded bone marrow-derived cells as major providers of the PrPc and PrPSc detected on FDCs. However, the involvement of non-haematopoietic cells (eg: muscle, endothelial, epithelial or nerve cells) cannot be excluded. We will use novel approaches to provide important information on FDC biology and their involvement in TSE pathogenesis. In particular we will address the following objectives: O-1: Do FDCs express PrPc or acquire it from other host cells? O-2: Do FDCs replicate TSE agents, or acquire them from other infected host cells? Increased understanding of the FDCs involvement in TSE pathogenesis may aid the development of therapeutic strategies.