Transcription profiling of mouse model of Lyme disease

The murine model of Lyme disease provides a unique opportunity to study the localized host response to similar stimulus, B. burgdorferi, in the joints of mice destined to develop severe arthritis (C3H) or mild disease (C57BL/6). Pathways associated with the response to infection and the development of Lyme arthritis were identified by global gene expression patterns using oligonucleotide microarrays. A robust induction of IFN responsive genes was observed in severely arthritic C3H mice at one week of infection, which was absent from mildly arthritic C57BL/6 mice. In contrast, infected C57BL/6 mice displayed a novel expression profile characterized by genes involved in epidermal differentiation and wound repair, which were decreased in the joints of C3H mice. These expression patterns were associated with disease state rather than inherent differences between C3H and C57BL/6 mice, as C57BL/6-IL10-/- mice infected with B. burgdorferi develop more severe arthritis that C57BL/6 mice and displayed an early gene expression profile similar to C3H mice. Gene expression profiles at two and four weeks post infection revealed a common response of all strains that was likely to be important for the host defense to B. burgdorferi and mediated by NF-kB-dependent signaling. The gene expression profiles identified in this study add to the current understanding of the host response to B. burgdorferi and identify two novel pathways that may be involved in regulating the severity of Lyme arthritis. Experiment Overall Design: Expression profiling of ankle tissues of C3H, C57BL/6, and C57BL/6-IL10-/- mice infected with B. burgdorfer (0, 1, 2, and 4 weeks post-infection)莱姆病（Lyme disease）小鼠模型为研究宿主针对同源刺激物伯氏疏螺旋体（B. burgdorferi）的局部宿主应答提供了独特契机：实验小鼠分为两类，分别会发展为重度关节炎（C3H品系）或轻度病症（C57BL/6品系）。本研究通过寡核苷酸微阵列（oligonucleotide microarray）分析全基因组基因表达谱，鉴定出与伯氏疏螺旋体感染应答及莱姆关节炎发病相关的信号通路。感染后第1周，重度关节炎表型的C3H小鼠中可见干扰素（IFN）应答基因的显著上调，而轻度病症的C57BL/6小鼠则无此类表达变化。与之相反，感染后的C57BL/6小鼠呈现出独特的基因表达谱：以表皮分化与伤口修复相关基因为特征，而此类基因在C3H小鼠的关节组织中表达下调。此类基因表达谱与疾病严重程度相关，而非C3H与C57BL/6小鼠的固有遗传差异：感染伯氏疏螺旋体的C57BL/6-IL10基因敲除（IL10-/-）小鼠，其关节炎严重程度高于普通C57BL/6小鼠，且早期基因表达谱与C3H小鼠相似。感染后第2、4周的基因表达谱分析显示，所有品系小鼠均存在共同的感染应答：该应答可能对宿主抵抗伯氏疏螺旋体至关重要，且由核因子κB（NF-κB）依赖型信号通路介导。本研究鉴定的基因表达谱深化了当前学界对宿主抵抗伯氏疏螺旋体应答的认知，并发现了两条可能参与调控莱姆关节炎严重程度的全新信号通路。实验整体设计：对感染伯氏疏螺旋体（B. burgdorferi）的C3H、C57BL/6及C57BL/6-IL10基因敲除小鼠的踝关节组织进行基因表达谱分析（感染后0、1、2、4周）。