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

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.