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Genetic control of immune response to Listeria infection

李斯特菌感染免疫反应的基因控制

基本信息

批准号：
7877285
负责人：
Victor L Boyartchuk
金额：
$ 1.9万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-14 至 2010-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7877285
关键词：
Affect Bioterrorism CXCL11 gene Candidate Disease Gene Chromosome Mapping Chromosomes, Human, Pair 13 Chromosomes, Human, Pair 5 Classification Collection Congenic Animals Congenic Mice Data Disease susceptibility Elements Exposure to Food Gene Pool Gene Transfer Techniques Genes Genetic Genetic Polymorphism Genetic Variation Goals Gram-Positive Bacteria Hand Human Human Genetics Immune response Inbred Strains Mice Individual Infection Intravenous Listeria monocytogenes Listeriosis Location Maps Modeling Mouse Strains Outcome Population Predisposition Public Health Quantitative Trait Loci Regulation Research Personnel Resistance Risk Role Survival Analysis Transgenic Organisms Variant base chemokine foodborne pathogen gene discovery gene function genetic analysis immune function improved in vivo pathogen positional cloning programs research study response tool

项目摘要

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. Wewill 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. Wewill 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.

尽管公共卫生状况稳步改善，但从集中的食品生产到潜在的生物恐怖主义使接触食源性病原体的风险很高。在人类中，对感染的免疫应答的差异是由每种免疫应答的独特等位基因组合决定的。单独的.我们的长期目标是了解免疫功能的变化程度，这种变异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细菌，它既是重要的人类病原体，被证明是研究免疫功能的工具然而，研究对L. 单核细胞增多症感染的人群。另一方面，近亲繁殖的小鼠在遗传上是易于处理，并对单核细胞增生李斯特菌感染表现出广泛的敏感性。对于我们的研究对L.单核细胞增多症感染，我们选择敏感的BALB/cByJ，抗性，C57 BL/6 ByJ，小鼠品系。我们分析了这些菌株的F2后代的存活率，单增李斯特菌的静脉感染鉴定了两个主要的数量性状位点（QTLs），Listrl 5号染色体和13号染色体上的Listr 2。我们目前的目标是进行基因的定位克隆控制这些基因座中所含的对单核细胞增多性李斯特菌感染的不同应答。实现这一我们将： 1.好地图L。单核细胞增多症易感基因座我们将进行广泛的遗传和表型分析，检查我们的同类小鼠品系，减少基因座的大小并定义它们的边界。 2.识别候选人L。单核细胞增多症敏感性基因可能控制的多态性基因对L.单核细胞增多症感染将通过定位克隆以及假设驱动的策略 3.确定多态性基因在控制L.单核细胞增多症我们将建立 CXCL 11在使用转基因方法控制单核细胞增生李斯特菌感染中的决定性作用。在此外，我们还将建立分析其他候选人的框架。