The extent and limits of natural transformation in Haemophilus influenzae

流感嗜血杆菌自然转化的程度和限制

• 批准号: 8236110
• 负责人: Joshua Chang Mell
• 金额: $ 0.79万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 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/8236110
• 关键词: AIDS/HIV problem; Address; Alleles; Antibiotic Resistance; Bacteria; Bacterial Chromosomes; Bacterial Meningitis; Bacterial Pneumonia; Biochemical; Cells; Chromosomes; Clinical; Competence; DNA; DNA Sequence; DNA Sequence Rearrangement; Data Set; Disease; Elderly; Environment; Epidemiologic Studies; Epitopes; Eukaryota; Evaluation; Event; Evolution; Explosion; Frequencies; Funding; Genes; Genetic; Genetic Recombination; Genetic Variation; Genome; Genomics; Haemophilus influenzae; Haemophilus influenzae type b bacteria; Host Defense; Human; Individual; Infant; Life; Link; Malaria; Measurement; Measures; Meningitis; Mismatch Repair; Molecular; Molecular Genetics; Mutation; Natural Selections; Pathway interactions; Pneumonia; Population Genetics; Property; Public Health; Recombinants; Recording of previous events; Reproduction; Research; Role; Route; Serotyping; Surface; Surveys; System; Therapeutic Intervention; Upper respiratory tract; Vaccines; Variant; Virulence Factors; Virulent; Work; burden of illness; cell transformation; ear infection; genome sequencing; genome wide association study; homologous recombination; novel; pathogen; pathogenic bacteria; public health relevance; research study

Bacterial meningitis and pneumonia are responsible for a large worldwide disease burden, greater than other better-funded pathogenic diseases like HIV/AIDS and malaria. One of these pathogens, Haemophilus influenzae, inhabits the upper respiratory tract of most people, usually with no negative effect, but can cause several diseases¿including meningitis, pneumonia, and ear infections¿in infants, the elderly, and immunecompromised individuals. Like many other bacterial pathogens, H. influenzae can consume DNA by transporting it into their cells, breaking it down and reusing the subunits. But some of this DNA can recombine with a cell¿s own chromosome, interchanging versions of genes and adding or deleting genes. This natural competence mechanism allows related bacteria living in the same host to share genes, hastening their adaptation to host defenses and therapeutic interventions. The proposed research will link molecular studies of transformation with epidemiological studies of natural genetic diversity by experimentally measuring the chromosome-wide consequences of natural transformation. I will use the genomic DNA of clinical isolates to transform the chromosomes of competent recipient cells, and I will then apply massively parallel DNA sequencing to measure the extent and limits of natural transformation. I will use two complementary approaches: (1) measure the extent of transformation in a set of individual recombinant clones, and (2) measure the frequency of transformation across the chromosome from cultures of transformed cells. This research will be the first comprehensive experimental evaluation of genetic exchange in a human pathogenic bacterium (or any bacteria).

细菌性脑膜炎和肺炎是造成全球疾病负担的主要原因， 艾滋病和疟疾等病原性疾病的资金更充足。这些病原体之一，嗜血杆菌 流感，栖息在大多数人的上呼吸道，通常没有负面影响，但可以引起 几种疾病包括脑膜炎，肺炎和婴儿，老年人和免疫受损的耳部感染 个体 与许多其他细菌病原体一样，H.流感病毒可以通过将DNA运送到它们的细胞中来消耗DNA， 分解并重新使用子单元。但其中一些DNA可以与细胞自身的DNA重组， 染色体，互换基因版本以及添加或删除基因。这种天生的能力 这种机制允许生活在同一宿主中的相关细菌共享基因，加速它们对宿主的适应 防御和治疗干预。 拟议的研究将把转化的分子研究与自然感染的流行病学研究联系起来。 通过实验测量自然转化的染色体范围的结果来研究遗传多样性。 我将使用临床分离株的基因组DNA转化感受态受体细胞的染色体， 然后，我将应用大规模并行DNA测序来测量自然的程度和限制。 转型我将使用两种互补的方法：（1）在一组 单个重组克隆，和（2）测量来自 转化细胞的培养物。这项研究将是第一个全面的实验评估遗传 在人类致病细菌（或任何细菌）中的交换。