Evolution of the Bordetellae from Commensals to Pathogens

博德特氏菌从共生菌到病原体的进化

• 批准号: 7886472
• 负责人: Eric T Harvill
• 金额: $ 38.48万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-03 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886472
• 关键词: Acute; Acute Disease; Address; Animals; Antibodies; Antigens; Blood Circulation; Bordetella; Bordetella bronchiseptica; Bordetella pertussis; Characteristics; Collection; Complex; DNA Resequencing; Data; Disease; Disease Outbreaks; Epidemic; Epidemiology; Event; Evolution; Exclusion; Failure; Genes; Genetic; Genome; Human; Immune; Immunity; Infection; Light; Mediating; Modeling; Mutation; Nature; Organism; Pathology; Pertussis; Pertussis Toxin; Phylogenetic Analysis; Phylogeny; Population; Population Study; Process; Publishing; Resistance; Respiratory System; Respiratory tract structure; Role; Shapes; Testing; Theoretical model; Time; Tropism; Virulence; Virulence Factors; Virulent; Work; Zoonoses; base; commensal animal; cross immunity; epidemiological model; infectious disease evolution; interdisciplinary approach; interest; mathematical model; mouse model; pathogen; pressure; progenitor; research study; respiratory; success; theories; transmission process

Understanding the events involved in the emergence of human pathogens from animal commensals/pathogens is important to our ability to confront their increasingly frequent outbreak. In an intriguing experiment of nature, the persistent commensal of a broad range of animals, Bordetella bronchiseptica, gave rise independently to two closely related human pathogens, B. pertussis and B. parapertussis. Both organisms are highly contagious, cause acute disease with high pathology and display strong resistance to antibody-mediated clearance, characteristics not observed in their common progenitor. We have recently shown that B. pertussis uses Pertussis Toxin (PTx) to avoid rapid antibody-mediated clearance, allowing this organism to infect immune hosts; a defining characteristic of B. pertussis. Paradoxically, B. parapertussis causes the same disease in the same host, and contains the genes for PTx but does not express them. The historical view of the apparent convergent evolution towards the ability to infect humans is unable to explain this. Another paradox of the bordetellae is the very existence, and remarkable success, of these two very closely related organisms in the same host populations. Evolutionary theory would predict that two such closely related organisms should compete via immune-mediated pressures within the host population. In our efforts to explain these observations we have proposed that, in addition to selection for optimal interactions with their hosts, the evolution of the bordetellae has been largely shaped by immune-mediated competition between strains that inhabit the same host population. This model fits with the observations that B. bronchiseptica infects all the animals around us but only rarely infects humans, and often those that are immunodeficient. Our preliminary data show that B. bronchiseptica is indeed sensitive to immune-cross protection and rapidly eliminated from B. pertussis-immune animals. Thus the exclusion of B. bronchiseptica from most healthy humans is the result of the high level of B. pertussis-immunity. However B. pertussis and B. parapertussis, both closely related to B. bronchiseptica, have coexisted within the same human populations, often at the same time. Here we offer the central hypothesis that immune-mediated competition shapes the evolution of the bordetellae and, by extension, that B. parapertussis and B. pertussis are under strong selective pressure for the loss of cross reactive antigens. We use our experimental infection model to directly examine cross-immunity and the effects of expression of cross-reactive antigens. We also extend our published MLST based phylogeny to examine the sequence of a number of antigenic genes across a population of closely related Bordetella isolates from humans and animals. Our phylogenetic studies have identified sequence types that infect both humans and animals. Using our 454 machine we will efficiently sequence the entire genomes of these strains to examine the effects of immune- mediated pressures at the genome level. Finally, these data will parameterize models of the within- and between-host dynamics of these reemerging human pathogens. Project Narrative: This proposal uses a multidisciplinary approach to examine the evolution of a set of closely related respiratory pathogens. The independent emergence of two of the most important human respiratory pathogens from this set of subspecies provides an extraordinary experiment of nature that will allow us to examine some of the most important questions regarding the evolution of infectious diseases and the emergence of human pathogens from zoonoses.

了解来自动物共生/病原体的人类病原体涉及的事件是 对于我们面对越来越频繁爆发的能力至关重要。在一个有趣的自然实验中 多种动物Bordetella支气管肢体的持续共同持续地产生了 两种密切相关的人类病原体，百日咳B. b. paropertussis。两种生物都具有高度传染性， 引起急性疾病，具有高病理学，表现出对抗体介导的清除率的强烈抗性， 在其公共祖细胞中未观察到的特征。我们最近表明百日咳B. 百日咳毒素（PTX）避免快速抗体介导的清除率，使该生物可以感染免疫 主持人；百日咳B。的定义特征。矛盾的是，B. parapertuss在 同一主机，并包含PTX的基因，但不表达它们。明显的历史观点 对感染人类的​​能力的融合进化无法解释这一点。另一个悖论 Bordetelae是这两个非常紧密相关的生物的存在和杰出的成功 同一寄主人群。进化论将预测两个这样的密切相关的生物应该 通过免疫介导的压力在宿主人群中竞争。在我们解释这些观察的努力中 我们建议，除了选择与宿主的最佳相互作用外， Bordetelae在很大程度上受到了居住在同一宿主的菌株之间的免疫介导的竞争的影响 人口。该模型符合观察到的，B。支气管肢体会感染我们周围的所有动物，但 只有很少感染人类，通常是免疫缺陷的人。我们的初步数据表明B。 支气管肽确实对免疫 - 交叉保护敏感，并迅速从百日咳芽孢杆菌中消除 动物。因此。 百日咳 - 免疫力。然而 通常同时同时同时共存。在这里，我们提供了一个中心假设 免疫介导的竞争塑造了Bordetelae的演变，并扩展了B. parapertussis 以及百日咳B.百日咳在强大的选择压力下，损失了交叉反应性抗原。我们使用我们的 实验感染模型直接检查跨免疫力和交叉反应的表达影响 抗原。我们还扩展了我们发表的基于MLST的系统发育，以检查许多的序列 来自人类和动物的密切相关的Bordetella分离株种群中的抗原基因。我们的 系统发育研究已经确定了感染人类和动物的序列类型。使用我们的454 机器我们将有效地测序这些菌株的整个基因组，以检查免疫的影响 基因组水平的介导压力。最后，这些数据将参数化 - 内部和内部的模型 这些重新体现的人类病原体的主持动力学之间。项目叙述： 该提案使用多学科的方法来检查一组密切相关的演变 呼吸道病原体。两种最重要的人类呼吸道的独立出现 这组亚种的病原体提供了一个非凡的自然实验，将允许 我们要研究有关传染病进化的一些最重要的问题 以及人畜共患病的人类病原体的出现。