Genetic control of immune response to Listeria infection

李斯特菌感染免疫反应的基因控制

• 批准号: 7032724
• 负责人: Victor L Boyartchuk
• 金额: $ 36.51万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032724
• 关键词: Listeria; Listeria infections; bacteria infection mechanism; bacterial cytopathogenic effect; bacterial genetics; gene expression; gene rearrangement; genetic mapping; genetic polymorphism; genetic regulation; genetic screening; genetic strain; genetic susceptibility; genetically modified animals; genotype; immune response; immunologic assay /test; inbreeding; laboratory mouse; phenotype; positional cloning; quantitative trait loci; recombinant DNA; transfection /expression vector

DESCRIPTION (provided by applicant): Despite steady improvements in public health, factors ranging from centralized food manufacturing to potential bioterrorism keep the risk of exposure to foodborne pathogens high. In the human population, differences in immune response to infection are determined by the unique allelic combinations of each individual. Our long term goal is to understand the extent of variation in immune function and to determine how this variation affects the course and outcome of infection. Listeria monocytogenes is a gram positive bacterium which is both an important human pathogen and a proven tool to study immune function. It is however difficult to study the genetic control of sensitivity to L. monocytogenes infection in human populations. Inbred strains of mice, on the other hand, are genetically tractable and display a wide range of sensitivities to L monocytogenes infection. For our studies of the genetic control of susceptibility to L. monocytogenes infection, we selected the sensitive, BALB/cByJ, and resistant, C57BL/6ByJ, strains of mice. Our analysis of the survival of F2 progeny of these strains following intravenous infection with L monocytogenes identified two major quantitative trait loci (QTLs), Listrl on chromosome 5 and Listr2 on chromosome 13. Our current goal is to perform positional cloning of the genes controlling the differential response to L monocytogenes infection contained in these loci. To achieve this we will: 1. Fine map the L. monocytogenes susceptibility loci. We will perform extensive genetic and phenotypic examination of our congenic mouse lines, decrease the size of the loci and define their boundaries. 2. Identify candidate L. monocytogenes sensitivity genes Polymorphic genes that are likely to control differential sensitivity to L. monocytogenes infection will be identified by a combination of a positional cloning and a hypothesis driven strategies 3. Establish the role of polymorphic genes in control of L. monocytogenes infection. We will establish the definitive role of CXCL11 in control of L monocytogenes infection using transgenic approaches. In addition we will create the framework for analysis of additional candidates.

描述（由申请人提供）：尽管公共卫生状况稳步改善，但从集中食品生产到潜在的生物恐怖主义等因素使暴露于食源性病原体的风险居高不下。在人类群体中，对感染的免疫应答的差异由每个个体的独特等位基因组合决定。我们的长期目标是了解免疫功能的变化程度，并确定这种变化如何影响感染的过程和结果。单核细胞增生李斯特菌是一种革兰氏阳性菌，是一种重要的人类病原体，也是研究免疫功能的有效工具。然而，研究对L.单核细胞增多症感染的人群。另一方面，小鼠的近交系在遗传上是易驯服的，并且对单核细胞增多性李斯特菌感染显示出广泛的敏感性。为研究L.在单核细胞增多症感染后，我们选择了敏感的BALB/cByJ和抗性的C57 BL/6 ByJ小鼠品系。我们对这些菌株静脉内感染单核细胞增生李斯特菌后的F2后代的存活率进行了分析，确定了两个主要的数量性状位点（QTL），5号染色体上的Listr 1和13号染色体上的Listr 2。我们目前的目标是进行定位克隆的基因控制的差异反应，单核细胞增生李斯特菌感染这些位点。为了实现这一目标，我们将：1。好地图L。单核细胞增多症易感基因座我们将对我们的同类小鼠品系进行广泛的遗传和表型检查，减小基因座的大小并确定它们的边界。2.识别候选人L。单核细胞增多症敏感性基因可能控制对李斯特菌的差异敏感性的多态性基因。单核细胞增多症感染将通过定位克隆和假设驱动策略的组合来鉴定3。确定多态性基因在控制L.单核细胞增生感染。我们将建立明确的作用，CXCL 11在控制单核细胞增生李斯特菌感染转基因的方法。此外，我们还将创建用于分析其他候选人的框架。