Genetics of Listeria induced changes in gene expression

描述(申请人提供)：哺乳动物宿主，从近亲繁殖的小鼠品系到人类，对各种细菌感染表现出广泛的表型反应。在小鼠身上引起这种差异反应的病原体之一是单核细胞增生性李斯特氏菌，这是一种革兰氏阳性细菌，是食物中毒的常见来源。之前的研究已经证实，免疫反应的差异通常是由基因控制的。免疫反应的差异可以用各种读数来表征，从基因表达的变化到疾病的结果。目前，基因表达数据是描述生物系统最全面的方法。此外，基因表达值可直接用于遗传数量性状定位实验。因此，通过监测对感染的差异转录反应，我们可以识别和表征对控制感染至关重要的分子。为了实现这一目标，我们将在感染单核细胞增多性李斯特菌后，对不同易感近交系小鼠的基因表达谱进行全基因组表征。 为了了解基因表达的变化如何影响免疫功能，我们必须区分主要差异和次要差异。初级表达差异是由基因座本身的遗传多态引起的，它直接影响基因转录本的水平。因此，次要差异是那些反映上游功能或表达差异的差异。我们将使用一种新的重组近亲交配表达图谱方法来区分对单核细胞增多性李斯特菌具有不同敏感性的小鼠品系中基因表达的原发和继发变化。我们的初步研究将确定对感染做出不同调控的分子。此外，它将使我们能够改进我们的方法，以便未来对感染疾病过程中不同易感宿主的基因表达变化进行全面研究。识别主要基因表达的变化将导致识别控制基因表达的遗传多态。此外，这些主要的表达差异将作为构建感染反应的多层转录图谱的起点。我们希望利用这一图谱来确定治疗传染病的新的治疗靶点。

DESCRIPTION (provided by applicant): Mammalian hosts, from inbred mouse strains to humans, display a wide range of phenotypic responses to various bacterial infections. One of the pathogens eliciting such differential responses in mice is Listena monocytogenes, a Gram-positive bacterium which is a common source of food poisoning. Previous studies have established that differences in immune response are often genetically controlled. Differences in immune response can be characterized using a variety of readouts, from gene expression changes to disease outcome. Currently, gene expression data is the most comprehensive way to describe a biological system. In addition, gene expression values can be used directly in genetic quantitative trait mapping experiments. Therefore, by monitoring differential transcriptional responses to infection, we can identify and characterize molecules critical for control of infection. To achieve this goal we will perform genome-wide characterization of gene expression profiles in differentially susceptible inbred mouse strains following infection with Listeria monocytogenes. To understand how changes in gene expression affect immune function, we have to differentiate between primary and secondary differences. Primary expression differences are caused by genetic polymorphisms at the gene locus itself, which directly affect the level of the gene transcript. Accordingly, secondary differences are those which reflect upstream functional or expression differences. We will use a novel Recombinant Inbred expression mapping approach to differentiate between primary and secondary changes in gene expression in mouse strains differentially susceptible to Listeria monocytogenes infection. Our pilot study will identify molecules differentially regulated in response to infection. Furthermore, it will allow us to refine our methodology for a future comprehensive study of changes in gene expression in differentially susceptible hosts over the course of the infectious disease. Identification of primary gene expression changes will lead to identification of genetic polymorphisms controlling gene expression. In addition, these primary expression differences will serve as starting points for building a multilayer map of transcriptional responses to infection. We hope to use this map to identify novel therapeutic targets for treatment of infectious diseases.