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，特别是那些感染多个宿主物种并表现出“溢出”到新宿主的疾病，了解病原体多样性产生和动态的机制和过程至关重要。基因和基因组多样性，以及相关的表型和功能，是在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宿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异在现行种群和生态系统条件下的适应性。迫切需要了解分散的多宿主种群中病原体动态和多样性的驱动因素。野生啮齿动物种群中的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。与啮齿动物相关的巴尔通体物种具有极高的遗传多样性，在宿主种群中流行率高（约40%），并包括与人类疾病相关的几种物种。在欧洲种群中，至少有4种具有不同水平的基因型多样性，基因型表现出不同水平的宿主特异性。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被随机打包到噬菌体颗粒中，形成了一种极其有效的基因转移机制。跳蚤媒介似乎在促进基因横向转移方面起着关键作用。迄今为止的研究主要集中在不同基因型的宿主特异性上。然而，其他关键特征，如感染长度和种在种间相互作用中的竞争能力，也有助于病原体在碎片化种群中持续存在的能力。该项目将使用新的和存档的水鼠种群样本来研究巴尔通体多样性的产生和动态。过去20年的研究提供了无与伦比的超种群动态知识（例如瓶颈，灭绝-再定居）。检测到的三种巴尔通体表现出负相互作用，共同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)利用多位点序列分析（MLSA）和全基因组测序方法量化三种巴尔通体种内多样性的时空格局；(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、宿主特异性和宿主特异性）。(3)确定不同巴尔通体的时空动态如何受到宿主连通性、替代宿主分布和共感染等因素的影响。本项目适合对空间生态学、疾病生态学和景观遗传学有兴趣的具有分子生态学或流行病学背景和数值技能的学生。该项目将与正在进行的水田鼠超种群实地研究一起进行。学生将使用下一代测序方法和分层空间模型来解释采样过程中所有阶段检测的不确定性。学生将在实验室技能、基因组和遗传数据分析以及高级统计建模方面接受全面培训，从而有可能从病原体检测数据中去除采样噪声

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