Ecological and genetic contributions to the spread of resistance in pneumococcus

生态和遗传对肺炎球菌耐药性传播的贡献

• 批准号: 8558619
• 负责人: William Hanage
• 金额: $ 59.77万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8558619
• 关键词: Academy; Address; American; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Data; Development; Disease; Ecology; Environment; Epidemiology; Event; Exhibits; Failure; Genes; Genetic; Genetic Materials; Genetic Recombination; Genome; Genomics; Goals; Health; High Prevalence; Human; Immunoglobulin Switch Recombination; Infant; Intervention; Investigation; Knowledge; Laboratories; Lead; Link; Methods; Microbiology; Mission; Molecular; Molecular Epidemiology; Mutation; Outcome; Persons; Pneumococcal Infections; Population; Populations at Risk; Prevalence; Process; Property; Public Health; Recording of previous events; Research; Resistance; Resistance development; Rest; Role; Sampling; Serotyping; Streptococcus pneumoniae; Testing; Therapeutic Agents; Time; Vaccination; Vaccine Antigen; Vaccines; Variant; Work; age group; bacterial resistance; base; cost; expectation; fitness; genome sequencing; homologous recombination; improved; innovation; novel; novel vaccines; pathogen; population based; prevent; public health relevance; resistant strain; success

DESCRIPTION (provided by applicant): There is a fundamental gap in our knowledge of how antibiotic resistant bacteria emerge and spread, and the ecological factors that favor their success. The continued existence of this gap is an important problem in devising better strategies of antibiotic stewardship and targeting them at the population - either host or bacteria - where they will have the greatest effect. The long-term goal of this application is the development of such strategies. Tracking resistance as it emerges, including ultimately unsuccessful variants that lead to evolutionary dead-ends, is a powerful way of identifying lineages and features associated with success. The objective of this application is to study the re-emergence of resistance in the pneumococcus following implementation of an effective vaccine that targets the great majority of resistant strains of this pathogen. The central hypothesis is that emerging resistant strains will have been present, though rare, before vaccination, and as they become more common they will come to predominate in regions with a large amount of antibiotic use. The applicants have formulated this hypothesis on the basis of preliminary data collected in their laboratories, and examination of data following previous vaccine introductions. The rationale for the proposal is that vaccination offers an opportunity to observe the emergence of resistance, and relate it both to features of the environments in which it emerges and the properties of the emerging strains themselves. The hypothesis will be addressed with three specific aims: 1) Define the origins of emerging resistant clones and their relationship to pre-existing populations; 2) Define ecological factors associated with the emergence of resistance in different regions; and 3) Define genomic properties of successful clones. Under the first aim, bacteria will be characterized by whole genome sequencing, with methods already in use in the PI's laboratory, will be used to determine the relationship between the prevaccine pneumococcal population, and resistant strains sampled by collaborators from a population of more than 29 million persons. The second aim will ask whether differences between regions in the prevalence of resistance, and the exact strains present, are best explained by differences in antibiotic use or other factors, applying methods developed by the co-I. The third aim will examine the genomes gathered in aim 1, to test for properties that could explain the success or failure of strains. The expectation is that these will reflect a history of recombination, which shuffles existing genetic material into novel combinations and which the PI has previously implicated in the spread of resistance in this pathogen. This approach is innovative in its combination of ecological and genomic analyses, and its emphasis on observing resistance as it emerges. The research is significant because it is expected to vertically advance understanding of the epidemiology of resistance in pneumococcus and other pathogens, and suggest means by which it may be limited through careful antibiotic stewardship.

描述（由申请人提供）：我们对抗生素耐药性细菌如何出现和传播以及有利于其成功的生态因素的了解存在根本性差距。这种差距的持续存在是设计更好的抗生素管理策略并将其针对人群（无论是宿主还是细菌）的一个重要问题，在那里它们将产生最大的效果。该应用程序的长期目标是开发此类策略。追踪出现的阻力，包括导致进化死胡同的最终不成功的变异，是识别与成功相关的谱系和特征的有效方法。本申请的目的是研究在实施针对肺炎球菌绝大多数耐药菌株的有效疫苗后，肺炎球菌耐药性的重新出现。中心假设是，新出现的耐药菌株在疫苗接种之前就已经存在，尽管很少见，随着它们变得越来越普遍，它们将在大量使用抗生素的地区占据主导地位。申请人根据其实验室收集的初步数据以及对先前疫苗引入后的数据检查提出了这一假设。该提案的基本原理是，疫苗接种提供了观察耐药性出现的机会，并将其与耐药性出现的环境特征以及新出现的菌株本身的特性联系起来。该假设将通过三个具体目标来解决：1）定义新出现的抗性克隆的起源及其与先前存在的种群的关系； 2）定义不同地区与抗性出现相关的生态因素； 3) 定义成功克隆的基因组特性。第一个目标是通过全基因组测序对细菌进行表征，该方法已在 PI 实验室中使用，将用于确定疫苗前肺炎球菌群体与合作者从超过 2900 万人中采样的耐药菌株之间的关系。第二个目标将询问，应用 co-I 开发的方法，是否可以通过抗生素使用或其他因素的差异来最好地解释区域之间耐药性流行率和存在的确切菌株的差异。第三个目标将检查目标 1 中收集的基因组，以测试可以解释菌株成功或失败的特性。预期这些将反映重组的历史，重组的历史将现有的遗传物质重组为新的组合，并且 PI 先前已暗示该重组与该病原体的抗性传播有关。这种方法的创新之处在于它结合了生态学和基因组分析，并强调观察出现的耐药性。这项研究意义重大，因为它有望纵向推进对肺炎球菌和其他病原体耐药性流行病学的了解，并提出通过仔细的抗生素管理来限制耐药性的方法。