Genome Evolution in Pathogens: The roles of predator-prey interactions

描述（由申请人提供）：病原体肠沙门氏菌是哺乳动物，爬行动物和鸟类肠道环境中常见的共生居民。像许多病原体一样，它在细胞外部（抗原）编码结构的基因上表现出极端的遗传变异。在大多数生物体中，人们认为在感染期间暴露于免疫系统为罕见的抗原类型提供了频率依赖性选择，从而允许逃逸。然而，与其他病原体不同的是，沙门氏菌在感染期间不会改变其主要的外膜多糖（o抗原）；相反，具有某些o抗原的血清型在感染宿主方面表现出特异性。这些数据表明，除了暴露于免疫系统之外，其他因素必须驱动沙门氏菌o型抗原变异的选择。我们认为，这种变异之所以得以维持，是因为它允许不同菌株的沙门氏菌在栖息于肠道的不同原生动物捕食者的环境中繁殖。初步数据表明，变形虫捕食者根据o抗原的差异对沙门氏菌血清型进行区分，不同的捕食者有不同的偏好。我们建议通过从鸟类和爬行动物肠道环境中分离和鉴定沙门氏菌及其共同捕食者来确定肠道原虫分布对沙门氏菌在肠道环境中定殖能力的影响程度。O-， H-和其他抗原在捕食者/猎物相互作用中的相对贡献将通过构建仅在rfb和/或fliC位点变化的等基因菌株来评估。通过研究捕食者在宿主中的非随机分布来评估捕食者与宿主的相互作用，这为多样化选择提供了基础。捕食者介导的猎物/宿主相互作用将通过使用荧光标记细菌在脊椎动物宿主内进行的竞争实验来评估；抗原生动物药物的使用将允许从局部肠道捕食者的影响中剥离与捕食无关的适应性特征。总之，这些实验验证了原生动物捕食可能在沙门氏菌和其他细菌在天然肠道环境中的分布中发挥作用的假设，以及o抗原变异在介导宿主血清特异性中的作用。

DESCRIPTION (provided by applicant): The pathogen Salmonella enterica is a common commensal inhabitant of mammalian, reptilian and avian intestinal environments. Like many pathogens, it shows extreme genetic variation at genes encoding structures presented on the outside of the cell (antigens). In most organisms, it is thought that exposure to the immune system during infection provides frequency-dependent selection for rare antigenic types, allowing escape. Yet unlike other pathogens, Salmonella does not alter its major outer-membrane polysaccharide (the O-antigen) during infection; on the contrary, serovars with certain O-antigens show specificity in terms of which hosts they will infect. These data show that factors other than exposure to the immune system must drive selection for variability at the Salmonella O-antigen. We propose that this variation is maintained because it allows different strains of Salmonella to prosper in environments which harbor different suites of protozoan predators which inhabit the intestine. Preliminary data show that amoeboid predators discriminate among Salmonella serovars based on differences in their O-antigens, and that different predators have different preferences. We propose to determine the degree to which the distribution of intestinal protozoa influences the ability of Salmonella to colonize the gut environment via isolation and characterization of Salmonella and their co-resident predators from avian and reptilian intestinal environments. The relative contributions the O-, H- and other antigens in predator/prey interactions will be assessed by the construction of isogenic strains that vary only at the rfb and/or fliC loci. Predator/host interactions will be assessed by examining the non-random distribution of predators among hosts, which provide the foundation for diversifying selection. The prey/host interaction - as mediated by the predator - will be assessed by competition experiments performed inside vertebrate hosts using fluorescently-tagged bacteria; the use of anti-protozoan drugs will allow the dissection of adaptive traits unrelated to predation from the effect of local intestinal predators. In total, these experiments test the hypothesis that protozoan predation may play a role in the distribution of Salmonella and other bacteria among natural intestinal environments, and the role of variability at the O-antigen in mediating host-serovar specificity.