Lyme Disease Diagnosis with Host Gene Expression Arrays

描述（由申请人提供）：莱姆病是美国最流行的媒介传播疾病，由螺旋体伯氏疏螺旋体感染引起。早期感染的抗生素治疗通常是治愈性的。如果不治疗，这种疾病可能会发展为更慢性的神经系统和风湿性表现，因此，莱姆病的有效管理取决于早期诊断。目前，诊断是基于临床表现和血清学检测。最常用的血清学检测方法在疾病早期缺乏灵敏度，缺乏标准化，实验室内和实验室间的差异和高假阳性率。因此，患者经常被多次检测，过度检测和过度诊断（或误诊）的趋势很大。该项目的一个长期目标是开发一种新的诊断方法，该方法基于暴露于B诱导的宿主基因表达的改变。burgdorferi。宿主整体基因表达反映了宿主对特定病原体的反应，可能有可能提供这种感染的证据。我们假设B.伯氏菌感染诱导宿主基因表达的改变。利用差异基因表达分析，我们提出了确定宿主基因的表达被改变的B。伯氏感染然后，该基因组可以用作B的指示物。临床标本中的伯氏菌感染。提出了以下具体目标：1）感染B后宿主基因表达的变化。将在鼠模型中评估伯氏螺旋体。小鼠将感染B。通过微阵列分析测量感染的动物和对照动物之间的mRNA表达差异; 2）将从健康供体分离的外周血单核细胞（PBMC）暴露于B。将通过微阵列分析监测分离自莱姆病患者的PBMC中差异表达的基因; 3）将通过微阵列分析鉴定分离自莱姆病患者的PBMC中差异表达的基因。这些研究将包括急性、非播散性早期疾病、早期播散性感染和莱姆关节炎患者。这里提出的研究应该导致鉴定宿主中在B期间表达被修饰的那些基因。伯氏感染这些信息，反过来，可以用来设计基于宿主基因的莱姆病诊断检测活动B。伯氏感染

DESCRIPTION (provided by applicant): Lyme disease, the most prevalent vector-borne disease in the United States, is caused by infection with the spirochete, Borrelia burgdorferi. Antibiotic treatment during early infection is generally curative. Untreated, the disease can progress to more chronic neurologic and rheumatologic manifestations and therefore, effective management of Lyme disease is dependent on early diagnosis. Currently, diagnosis is based on both clinical findings and serologic testing. The most commonly employed serologic assays suffer from lack of sensitivity during early disease, lack of standardization, intra- and inter-laboratory variation and a high false-positivity rate. As a result, patients are often tested multiple times and the tendency for overtesting and overdiagnosis (or misdiagnosis) is great. A long-term goal of this project is development of a novel diagnostic approach based on alterations in host gene expression induced by exposure to B. burgdorferi. Host global gene expression, reflecting responses of the host to a specific pathogen, may have the potential to provide evidence of such an infection. We hypothesize that B. burgdorferi infection induces modifications in host gene expression. Using differential gene expression analysis, we propose to identify host genes whose expression is altered by B. burgdorferi infection. This gene set can then be employed as an indicator for B. burgdorferi infection in clinical specimens. The following specific aims are proposed: 1) Variation in host gene expression on infection with B. burgdorferi will be assessed in a murine model. Mice will be infected B. burgdorferi and differences in mRNA expression between control and infected animals will be measured by microarray analysis; 2) Peripheral blood mononuclear cells (PBMCs) isolated from healthy donors will be exposed to B. burgdorferi or other potential blood-borne pathogens and differences in global gene expression will be monitored by microarray analysis; 3) Genes differentially expressed in PBMCs isolated from Lyme disease patients will be identified by microarray analysis. These studies will include patients with acute, non-disseminated early disease, early disseminated infection and Lyme arthritis. The studies proposed here should result in identification of those genes in the host whose expression is modified during B. burgdorferi infection. This information, in turn, can be used to design host gene-based Lyme disease diagnostics for the detection of active B. burgdorferi infection.