Understanding the generation and dynamics of Bartonella diversity, host specificity, vector specificity, and competitive ability in mixed infections

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。迫切需要了解在碎片化的多宿主种群中病原体动态和多样性的驱动因素。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个物种具有不同程度的基因多样性，并且不同的基因类型表现出不同的寄主专一性。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。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，也有助于病原体在分散的种群中持续存在。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。过去20年的研究提供了关于集合种群动态的无与伦比的知识(例如，瓶颈、灭绝-再殖民)。检测到的三种巴尔通氏菌呈现负相互作用，合并感染的个体和亚群发生的频率低于预期。为了研究这些时空动态的关键驱动因素，该项目将(1)使用多位点序列分析(MLSA)和全基因组测序方法量化三个巴尔通体物种内多样性的时空格局，(2)评估不同基因类型的表型属性(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)确定不同巴尔通体的时空动态如何受到宿主连通性、替代宿主的分布和联合感染的影响。该项目适合具有分子生态学或流行病学背景和数字技能的学生，他们对空间生态学感兴趣，疾病生态学和景观遗传学。该项目将与正在进行的水鼠集合种群实地研究相结合。学生将使用下一代测序方法和分层空间模型来说明在采样过程的所有阶段检测中的不确定性。学生将接受实验室技能、基因组和遗传数据分析以及高级统计建模方面的全面培训，以消除病原体检测数据中的采样噪声。

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. There is an urgent need to understand the drivers of pathogen dynamics and diversity in fragmented 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. 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 also contribute to a pathogen's ability to persist in fragmented populations. This project will use new and archived samples from water vole metapopulations to examine the generation and dynamics of Bartonella diversity. Studies over the last 20 years provide unparalleled knowledge of metapopulation dynamics (e.g. bottlenecks, extinction-recolonization). The three Bartonella species detected exhibit negative interactions, with coinfected individuals and subpopulations occurring less often than expected. To investigate the key drivers of these spatial and temporal dynamics, the project will (1) quantify spatio-temporal patterns of intraspecific diversity for the three Bartonella species using multi-locus sequence analysis (MLSA) and whole genome sequencing approaches, (2) assess phenotypic properties of different genotypes (host specificity, vector specificity, infection length, competitive ability in mixed infections) (3) determine how the spatial-temporal dynamics of different Bartonella are influenced by e.g. host connectivity, distribution of alternative hosts and coinfection.The project suits a student with a background in molecular ecology or epidemiology and numerical skills, who has interests in spatial ecology, disease ecology and landscape genetics. The project will be conducted in association with an ongoing field study of water vole metapopulations. The student will use next generation sequencing approaches and hierarchical spatial models to account for uncertainty in detection at all stages of the sampling process. The student will be given a thorough training in laboratory skills, the analysis of genomic and genetic data and advanced statistical modelling that make it possible to remove sampling noise from pathogen detection data