Understanding the generation and dynamics of Bartonella diversity in fragmented host populations

如果我们想要管理疾病风险，特别是对于感染多个寄主物种并表现出鲜为人知的对新宿主的“溢出”现象的疾病，了解病原体多样性的产生和动态所涉及的机制和过程是至关重要的。基因和基因组的多样性以及相关的表型和功能，是从基因组到生态系统的不同水平上运作的过程的结果。新的遗传变异可能通过允许感染新的寄主物种或改变毒力来改变宿主与病原体的相互作用。然而，它们随后的动态将取决于新变种在当前人口和生态系统条件下的适宜性。在当今的异质性景观中，宿主种群日益分散，迫切需要将病原菌遗传多样性的时空信息与动态流行病学模型联系起来，以探索影响空间结构多宿主种群中病原菌动态变化的关键因素。巴尔通体在野生啮齿动物种群中的感染是研究这些问题的理想模式系统。巴尔通体是一种通过跳蚤传播的细胞内细菌。与啮齿动物相关的巴尔通体物种表现出极高的遗传多样性，在宿主种群中的流行率很高(&gt；40%)，包括几个与人类疾病有关的物种。在欧洲种群中，至少有4个物种具有不同水平的基因多样性，并且基因类型表现出不同的寄主专一性水平。基因组分析表明，这些物种已经进化出促进多样性的策略，许多与宿主适应相关的基因随机包装成噬菌体颗粒，产生了一种极其有效的基因转移机制。物种内和物种间重组的证据经常被检测到。由于一些基因类型是相对宿主特有的，跳蚤载体似乎通过促进侧向基因转移发挥了关键作用。到目前为止，研究主要集中在不同基因类型的寄主特异性。然而，其他关键特征，如感染长度和种间相互作用中的竞争能力，已知在不同物种之间存在差异，也是决定病原体在空间结构种群中持续存在的能力的关键。该项目将使用来自水鼠集合种群的新的和存档的样本来研究巴尔通体多样性的产生和动态。水鼠形成离散的亚群，通过偶尔的扩散事件联系在一起，并表现出灭绝-重新定居的动态。这些种群与其他啮齿动物和跳蚤物种共存，群落多样性在低地和高地地区有所不同。过去15年的研究提供了集合种群历史的无与伦比的知识(如种群瓶颈、亚种群灭绝-重新殖民事件)。至少有三种巴尔通体感染这些种群。具体地说，该项目将(1)使用多位点序列分析(MLSA)来量化具有已知历史且宿主-媒介群落多样性不同的集合种群中的遗传和基因组结构多样性；(2)评估不同基因型的表型特性(宿主特异性、媒介特异性、感染长度、混合感染中的竞争能力)；(3)建立流行病学模型，用经验数据进行参数化，以探索病原体的动态和持久性；以及(4)将这些流行病学模型与关于基因型分布的时空数据联系起来。

Understanding the mechanisms and processes involved in the generation and dynamics of pathogen diversity is critical if we want to manage disease risk, especially for diseases that infect multiple host species and exhibit the poorly understood phenomenon of "spillover" to new hosts. Gene and genome diversity, and associated phenotypes and functionality, are a consequence of processes operating at varying levels from genomes to ecosystems. New genetic variants may alter host-pathogen interactions by allowing infection of new host species or changing virulence. However, their subsequent dynamics will depend on the fitness of the new variant in the context of the prevailing population and ecosystem conditions. In today's heterogeneous landscapes host populations are increasingly fragmented, and there is an urgent need to link spatio-temporal information on pathogen genetic diversity to dynamical epidemiological models to explore the key factors influencing pathogen dynamics in spatially structured multi-host populations. Bartonella infections in wild rodent populations are an ideal model system to examine these issues. Bartonella are intracellular bacteria that are transmitted by fleas. Rodent-associated Bartonella species exhibit extremely high genetic diversity, high prevalence within host populations (>40%), and include several species associated with human disease. Within European populations there are at least 4 species with differing levels of genotypic diversity, and genotypes exhibit varying levels of host specificity. Genomic analyses indicate that these species have evolved strategies to promote diversity, with many genes associated with host-adaptation packaged randomly into bacteriophage particles, generating an extremely effective mechanism for gene transfer. Evidence of recombination within and between species is frequently detected. As some genotypes are relatively host specific, flea vectors appear to have a key role by promoting lateral gene transfer. To date studies have focussed on host-specificity of different genotypes. However, other key traits such as infection length and competitive ability in interspecific interactions are known to vary between species and are also critical in determining a pathogen's ability to persist in spatially structured populations. This project will use new and archived samples from water vole metapopulations to examine the generation and dynamics of Bartonella diversity. Water voles form discrete subpopulations linked by occasional dispersal events and exhibit extinction-recolonisation dynamics. These populations coexist with other rodents and flea species, with community diversity varying between lowland and upland areas. Studies over the last 15 years provide unparalleled knowledge of metapopulation history (such as population bottlenecks, subpopulation extinction-recolonisation events). At least three Bartonella species infect these populations. Specifically the project will (1) use multi-locus sequence analysis (MLSA) to quantify genetic and genome structure diversity in metapopulations with a known history and that differ in host-vector community diversity; (2) assess phenotypic properties of different genotypes (host specificity, vector specificity, infection length, competitive ability in mixed infections); (3) construct epidemiological models, parameterised with the empirical data, to explore pathogen dynamics and persistence and (4) link these epidemiological models with spatial-temporal data on genotype distribution.