Carroll James A, Striebel James F, Race Brent, Phillips Katie, Chesebro Bruce
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
J Virol. 2015 Feb;89(4):2388-404. doi: 10.1128/JVI.02952-14. Epub 2014 Dec 10.
Gliosis is often a preclinical pathological finding in neurodegenerative diseases, including prion diseases, but the mechanisms facilitating gliosis and neuronal damage in these diseases are not understood. To expand our knowledge of the neuroinflammatory response in prion diseases, we assessed the expression of key genes and proteins involved in the inflammatory response and signal transduction in mouse brain at various times after scrapie infection. In brains of scrapie-infected mice at pre- and postclinical stages, we identified 15 previously unreported differentially expressed genes related to inflammation or activation of the STAT signal transduction pathway. Levels for the majority of differentially expressed genes increased with time postinfection. In quantitative immunoblotting experiments of STAT proteins, STAT1α, phosphorylated-STAT1α (pSTAT1α), and pSTAT3 were increased between 94 and 131 days postinfection (p.i.) in brains of mice infected with strain 22L. Furthermore, a select group of STAT-associated genes was increased preclinically during scrapie infection, suggesting early activation of the STAT signal transduction pathway. Comparison of inflammatory markers between mice infected with scrapie strains 22L and RML indicated that the inflammatory responses and gene expression profiles in the brains were strikingly similar, even though these scrapie strains infect different brain regions. The endogenous interleukin-1 receptor antagonist (IL-1Ra), an inflammatory marker, was newly identified as increasing preclinically in our model and therefore might influence scrapie pathogenesis in vivo. However, in IL-1Ra-deficient or overexpressor transgenic mice inoculated with scrapie, neither loss nor overexpression of IL-1Ra demonstrated any observable effect on gliosis, protease-resistant prion protein (PrPres) formation, disease tempo, pathology, or expression of the inflammatory genes analyzed.
Prion infection leads to PrPres deposition, gliosis, and neuroinflammation in the central nervous system before signs of clinical illness. Using a scrapie mouse model of prion disease to assess various time points postinoculation, we identified 15 unreported genes that were increased in the brains of scrapie-infected mice and were associated with inflammation and/or JAK-STAT activation. Comparison of mice infected with two scrapie strains (22L and RML), which have dissimilar neuropathologies, indicated that the inflammatory responses and gene expression profiles in the brains were similar. Genes that increased prior to clinical signs might be involved in controlling scrapie infection or in facilitating damage to host tissues. We tested the possible role of the endogenous IL-1Ra, which was increased at 70 days p.i. In scrapie-infected mice deficient in or overexpressing IL-1Ra, there was no observable effect on gliosis, PrPres formation, disease tempo, pathology, or expression of inflammatory genes analyzed.
胶质增生通常是神经退行性疾病（包括朊病毒病）的临床前病理表现，但这些疾病中促进胶质增生和神经元损伤的机制尚不清楚。为了拓展我们对朊病毒病神经炎症反应的认识，我们评估了瘙痒病感染后不同时间点小鼠脑中参与炎症反应和信号转导的关键基因和蛋白质的表达。在瘙痒病感染小鼠临床前和临床后的大脑中，我们鉴定出15个先前未报道的与炎症或STAT信号转导途径激活相关的差异表达基因。大多数差异表达基因的水平随感染后时间增加。在STAT蛋白的定量免疫印迹实验中，感染22L毒株的小鼠大脑在感染后94至131天，STAT1α、磷酸化STAT1α（pSTAT1α）和pSTAT3增加。此外，一组特定的STAT相关基因在瘙痒病感染临床前增加，表明STAT信号转导途径早期激活。比较感染瘙痒病毒株22L和RML的小鼠的炎症标志物表明，尽管这些瘙痒病毒株感染不同脑区，但大脑中的炎症反应和基因表达谱惊人地相似。内源性白细胞介素-1受体拮抗剂（IL-1Ra）作为一种炎症标志物，在我们的模型中被新鉴定为在临床前增加，因此可能在体内影响瘙痒病发病机制。然而，在接种瘙痒病病毒的IL-1Ra缺陷或过表达转基因小鼠中，IL-1Ra的缺失或过表达对胶质增生、抗蛋白酶朊病毒蛋白（PrPres）形成、疾病进程、病理学或所分析的炎症基因表达均未显示出任何可观察到的影响。
朊病毒感染在出现临床疾病迹象之前会导致PrPres沉积、胶质增生和中枢神经系统神经炎症。使用朊病毒病的瘙痒病小鼠模型评估接种后的不同时间点，我们鉴定出15个未报道的基因，这些基因在瘙痒病感染小鼠的大脑中增加，且与炎症和/或JAK-STAT激活相关。比较感染两种具有不同神经病理学的瘙痒病毒株（22L和RML）的小鼠表明，大脑中的炎症反应和基因表达谱相似。在临床症状出现之前增加的基因可能参与控制瘙痒病感染或促进对宿主组织的损伤。我们测试了内源性IL-1Ra的可能作用，其在感染后70天增加。在IL-1Ra缺陷或过表达的瘙痒病感染小鼠中，对胶质增生、PrPres形成、疾病进程、病理学或所分析的炎症基因表达均未显示出任何可观察到的值。
