Genetic control of immune response to Listeria infection

描述(申请人提供)：尽管公共卫生稳步改善，但从中央食品制造到潜在的生物恐怖主义等各种因素，使接触食源性病原体的风险很高。在人类群体中，对感染的免疫反应的差异是由每个个体独特的等位基因组合决定的。我们的长期目标是了解免疫功能的变异程度，并确定这种变异如何影响感染的过程和结果。单核细胞增多性李斯特菌是一种革兰氏阳性菌，是人类重要的病原体，也是研究免疫功能的有效工具。然而，研究人类人群对单核细胞增多性李斯特菌感染敏感性的遗传控制是困难的。另一方面，近交系小鼠在遗传上容易驯化，对L单核细胞增多症感染表现出广泛的敏感性。为了研究单核细胞增多性李斯特菌感染易感性的遗传控制，我们选择了敏感品系BALB/cByJ和抗性品系C57BL/6ByJ。我们对这些毒株静脉感染L后的F2代存活率进行了分析，发现了两个主要的数量性状基因座(QTL)，分别位于第5号染色体上的Listr1和13号染色体上的Listr2。我们目前的目标是对这些基因座上控制L感染差异反应的基因进行定位克隆。为此，我们将：1.精细定位单核细胞增多性李斯特菌易感基因座。我们将对我们的同源小鼠品系进行广泛的遗传和表型检查，减少基因座的大小并确定它们的边界。2.确定候选的单核细胞增多性李斯特氏菌敏感基因可能控制单核细胞增多性李斯特氏菌感染的差异敏感性的多态基因将通过定位克隆和假设驱动策略相结合来确定3.确定多态基因在控制单核细胞增多性李斯特氏菌感染中的作用。我们将利用转基因方法确定CXCL11在控制L单核细胞增多症感染中的决定性作用。此外，我们还将建立分析其他候选人的框架。

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.