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

如果我们想要管理疾病风险，特别是感染多个宿主物种并表现出对新宿主的“溢出”现象知之甚少的疾病，那么了解病原体多样性的产生和动态所涉及的机制和过程至关重要。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层次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宿主物种或改变毒力来改变宿主-病原体相互作用。然而，它们随后的动态将取决于新变异体在当前人口和生态系统条件下的适应性。在今天的异质景观宿主种群越来越分散，有一个迫切需要链接的时空信息病原体遗传多样性的动态流行病学模型，探索空间结构的多宿主种群的病原体动态的关键因素。野生啮齿动物群体中巴尔通体感染是研究这些问题的理想模型系统。巴尔通体是由跳蚤传播的细胞内细菌。啮齿动物相关巴尔通体物种表现出极高的遗传多样性，在宿主群体中的高流行率（>40%），并包括与人类疾病相关的几个物种。在欧洲人群中，至少有4个物种具有不同程度的基因型多样性，基因型表现出不同程度的宿主特异性。基因组分析表明，这些物种已经进化出了促进多样性的策略，许多与宿主适应相关的基因随机包装到噬菌体颗粒中，产生了一种非常有效的基因转移机制。物种内部和物种之间的重组证据经常被发现。由于某些基因型具有相对的宿主特异性，跳蚤载体似乎通过促进横向基因转移而发挥关键作用。迄今为止，研究集中在不同基因型的宿主特异性上。然而，其他关键性状，如感染长度和种间相互作用中的竞争能力，已知不同物种之间的变化，也是决定病原体的能力，坚持在空间结构的人口至关重要。该项目将使用新的和存档的水鼠集合种群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连接偶尔的扩散事件和表现出的防御-防御动态。这些种群与其他啮齿动物和跳蚤物种共存，低地和高地地区的群落多样性各不相同。过去15年的研究提供了关于集合种群历史（如种群瓶颈、亚群分离-分离事件）的无与伦比的知识。至少有三种巴尔通体感染这些人群。具体而言，该项目将（1）使用多位点序列分析（MLSA）来量化具有已知历史和宿主-载体群落多样性不同的集合种群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、载体特异性、感染长度、混合感染中的竞争能力）;（3）构建流行病学模型，用经验数据进行参数化，以探索病原体动态和持久性;（4）将这些流行病学模型与基因型分布的时空数据相联系。

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.