Diversity of Host Pathogen Interactions

宿主病原体相互作用的多样性

• 批准号: 8236991
• 负责人: Samuel I Miller
• 金额: $ 39.16万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236991
• 关键词: Affect; Alleles; Animal Model; Antibiotics; Bacteria; Bacterial Infections; Biological Assay; Burkholderia; Candidate Disease Gene; Categories; Cell Death; Cell Survival; Cell physiology; Cells; Centers of Research Excellence; Cessation of life; Chronic; Communicable Diseases; Computer Simulation; Databases; Disease; Emerging Communicable Diseases; Epidemiology; Etiology; European; Exhibits; Family; Francisella; Funding; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; HIV; Health; Heritability; Human; In Vitro; Individual; Infection; Inflammatory; Inflammatory Bowel Diseases; Internet; Knock-out; Knowledge; Life Style; Location; Malaria; Measurement; Measures; Messenger RNA; Methods; Microbiology; Morbidity - disease rate; Mus; Mutation; Natural Immunity; Nature; Parents; Pathogenesis; Phenotype; Population; Predisposition; Production; Proteins; Public Health; RNA Interference; RNA Splicing; Recording of previous events; Reproducibility; Resistance; Rheumatoid Arthritis; Salmonella; Series; Severities; Signal Pathway; System; Testing; Transgenic Mice; Validation; Variant; Virulence; Whole Organism; Work; Yersinia; base; biodefense; biosecurity; case control; clinical phenotype; comparative; cytokine; fitness; genome wide association study; genome-wide; human disease; interest; knock-down; lymphoblastoid cell line; monocyte; mortality; offspring; overexpression; pandemic disease; pathogen; pathogenic bacteria; research clinical testing; research study; response; therapy development; uptake; vaccine development

Despite improvements in public health, advancements in vaccines, and the development of many classes of antibiotics, infectious disease is still responsible for over a quarter of all deaths worldwide. However, even for the most devastating of pandemics, history demonstrates a large variability in the severity and duration of infection. Despite this, few examples of association between human polymorphism and susceptibility to bacteria are known. The goals of this project are to 1) identify aspects of bacterial infection in humans that exhibit heritable variation, 2) determine the genetic changes that are responsible, and 3) assess the relevance of this variation on the fitness of whole organisms. We are measuring intermediate phenotypes of susceptibility using cells derived from populations of apparently normal individuals. Assays of bacterial uptake, replication, and localization, and host-cell survival and cytokine production provide a quantitative, cellular picture of infection. Family-based association analyses are being used to correlate values from these assays with SNPs in candidate genes selected based on relevant cellular microbiology and on a genome-wide scale. Causation of the identified SNPs is being established by a combination of expression analysis, RNA interference, and overexpression experiments. Finally, relevance to health and disease will be measured using association analysis of clinical phenotypes and phenotypic measurements of transgenic mice.

尽管公共卫生有所改善，疫苗取得了进步，许多种类的疫苗也得到了发展， 尽管使用了抗生素，但传染病仍然是全球四分之一以上死亡的原因。但即使 对于最具破坏性的大流行病，历史表明其严重程度和持续时间存在很大的差异。 感染尽管如此，人类多态性与易感性之间的关联的例子很少， 细菌是已知的 该项目的目标是：1）确定人类细菌感染的各个方面， 变异，2）确定负责的遗传变化，3）评估这一变化的相关性， 整个生物体适应性的变化。我们正在测量易感性的中间表型 使用的细胞来源于明显正常的个体群体。细菌摄取，复制， 和定位，宿主细胞存活和细胞因子的产生提供了一个定量的细胞图像， 感染基于家族的关联分析被用于将这些测定的值与 基于相关细胞微生物学和全基因组规模选择的候选基因中的SNP。 通过结合表达分析、RNA干扰、基因突变和基因突变， 干扰和过表达实验。最后，将衡量与健康和疾病的相关性 使用转基因小鼠的临床表型和表型测量的关联分析。