Drifting to victory: resolving the paradox of M.tuberculosis evolution

走向胜利：解决结核分枝杆菌进化的悖论

• 批准号: 9089907
• 负责人: Caitlin S Pepperell
• 金额: $ 37.4万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089907
• 关键词: Accounting; Alleles; Antitubercular Agents; Automobile Driving; Benchmarking; Censuses; Cessation of life; Clinical; Clonal Evolution; Clonality; DNA; Data; Data Set; Development; Disease; Drug resistance in tuberculosis; ELF3 gene; Ecology; Epidemiology; Event; Evolution; Extinction (Psychology); Fertility; Foundations; Founder Effect; Frequencies; Genetic; Genetic Conjugation; Genetic Drift; Genetic Models; Genetic Recombination; Genetic Variation; Genomics; Genus Mycobacterium; Goals; HIV; Health; Horizontal Gene Transfer; Human; Incidence; Knowledge; Maintenance; Mating Types; Measures; Meiosis; Microbial Biofilms; Modeling; Mycobacterium smegmatis; Mycobacterium tuberculosis; Organism; Partner in relationship; Pattern; Phenotype; Population; Population Genetics; Process; Public Health; Publishing; Research; Resistance; Resolution; Risk; Role; Sampling; Shapes; Site; Source; Structure; System; Testing; Tuberculosis; Variant; Work; base; comparative; design; disability; genetic signature; genetic variant; genome-wide; genomic data; global health; innovation; insight; microbial; mycobacterial; pathogen; reproductive; research study; trait; transmission process

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (M.tb) infects a new human host every second. It is not known why M.tb is such a successful pathogen, and it is unexpected given the current understanding of how M.tb evolves. The long-term goal of this research is to identify ecological and evolutionary processes driving emergence and maintenance of pathogenic traits in microbial populations. The objective of this proposal is to understand effects of recombination and variable TB transmission on evolution of M.tb. The central hypothesis is: apparently paradoxical features of M.tb evolution are due to the unrecognized influence of cryptic recombination and extreme variability of TB transmission. The rationale for the proposed research is the central role of recombination and reproductive dynamics in shaping patterns of genetic diversity. Two specific aims will be used to test this hypothesis: 1) Characterize lateral gene transfer (LGT) among pathogenic mycobacteria; and 2) Quantify TB transmission variability and measure its effects on M.tb evolution. In Aim 1, patterns of recombination will be inferred from high resolution genomic data in natural populations of mycobacteria; LGT will be further characterized in an experimental system. In Aim 2, genomic and epidemiological data from a well-characterized M.tb meta- population will be analyzed for signatures of variability in TB transmission. Best fit population genetic models will also be identified for M.tb populations, and parameters of these models compared with benchmark values inferred from epidemiological data. By tackling the unexplored paradox of TB's persistence as a threat to global health despite apparent limitations on M.tb adaptability, the proposed project offers an innovative alternative to current perspectives on M.tb evolution. This research will provide greater insight into how M.tb evolves, which is needed to understand why these populations are so resilient, and ultimately to design better strategies of controlling or even eradicating TB. It will also open new avenues of research to identify effects of cryptic re- combination and heterogeneous transmission on evolution of other bacterial pathogens.

 描述（由申请人提供）：结核分枝杆菌（M.tb）每秒都会感染一个新的人类宿主。目前尚不清楚为什么结核分枝杆菌是一种如此成功的病原体，而且考虑到目前对结核分枝杆菌如何进化的了解，这是出乎意料的。这项研究的长期目标是确定驱动微生物种群致病性状出现和维持的生态和进化过程。该提案的目的是了解重组和可变结核病传播对结核分枝杆菌进化的影响。中心假设是：结核分枝杆菌进化的明显矛盾特征是由于结核病传播的隐秘重组和极端变异性的未被认识到的影响造成的。拟议研究的基本原理是重组和生殖动力学在塑造遗传多样性模式中的核心作用。将使用两个具体目标来检验这一假设：1）表征致病性分枝杆菌之间的横向基因转移（LGT）； 2) 量化结核病传播变异性并测量其对结核病演变的影响。在目标 1 中，将从分枝杆菌自然群体的高分辨率基因组数据推断重组模式； LGT 将在实验系统中进一步表征。在目标 2 中，将对来自特征明确的结核分枝杆菌亚群的基因组和流行病学数据进行分析，以了解结核病传播的变异特征。还将确定结核分枝杆菌人群的最佳拟合人群遗传模型，并将这些模型的参数与从流行病学数据推断的基准值进行比较。尽管结核病适应性明显受到限制，但通过解决结核病持续威胁全球健康这一尚未探索的悖论，拟议项目为当前结核病进化观点提供了一种创新的替代方案。这项研究将更深入地了解结核分枝杆菌如何演变，这有助于理解为什么这些人群具有如此强的适应力，并最终设计出更好的控制甚至根除结核病的策略。它还将开辟新的研究途径，以确定神秘重组和异质传播对其他细菌病原体进化的影响。