Evolution of the Bordetellae from Commensals to Pathogens

描述（由申请人提供）：了解人类病原体从动物病原体/病原体中出现所涉及的事件对于我们应对其日益频繁的爆发的能力至关重要。在一个有趣的自然实验中，广泛动物的持久性寄生虫，支气管败血波氏杆菌，独立地产生了两种密切相关的人类病原体，B。百日咳和B.副百日咳。这两种微生物都具有高度传染性，引起急性疾病，病理学程度高，对抗体介导的清除表现出很强的抵抗力，这些特征在它们的共同祖先中没有观察到。我们最近证明了B。百日咳使用百日咳毒素（PTx）来避免抗体介导的快速清除，从而使该微生物感染免疫宿主;这是B的定义特征。百日咳。巧合的是，B。副百日咳在同一宿主中引起相同的疾病，并且含有PTx的基因但不表达它们。历史上关于感染人类能力的明显趋同进化的观点无法解释这一点。博德特氏菌的另一个悖论是，这两种非常密切相关的生物在同一宿主种群中的存在和显著成功。进化理论预测，两个如此密切相关的生物体应该通过宿主群体内的免疫介导的压力进行竞争。在我们努力解释这些观察结果的过程中，我们提出，除了选择与宿主的最佳相互作用之外，博德特氏菌的进化在很大程度上是由居住在同一宿主群体中的菌株之间的免疫介导的竞争形成的。该模型与B.支气管败血症感染我们周围的所有动物，但很少感染人类，而且通常是那些免疫缺陷的人。我们的初步数据显示，B.支气管败血症确实对免疫交叉保护敏感，并迅速从B中消除。免疫百日咳的动物因此，排除B。大多数健康人的支气管败血症是高水平B的结果。百日咳免疫然而，B。百日咳和B.副百日咳，两者都与B密切相关。支气管败血症，在同一人群中共存，往往在同一时间。在这里，我们提供了一个中心假设，即免疫介导的竞争塑造了博德特氏菌的进化，并通过扩展，即B。副百日咳和B.百日咳患者在交叉反应性抗原丢失的强烈选择压力下。我们使用我们的实验感染模型来直接检查交叉免疫和交叉反应性抗原表达的影响。我们还扩展了我们发表的基于MLST的同源性，以检查来自人类和动物的密切相关的博德特氏菌分离株群体中的许多抗原基因的序列。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，我们将有效地对这些菌株的整个基因组进行测序，以在基因组水平上检查免疫介导的压力的影响。最后，这些数据将参数化这些重新出现的人类病原体的宿主内和宿主间动态模型 项目叙述：该提案采用多学科方法来研究一组密切相关的呼吸道病原体的演变。两种最重要的人类呼吸道病原体从这组亚种中独立出现，提供了一个非凡的自然实验，使我们能够研究有关传染病进化和人畜共患病中人类病原体出现的一些最重要的问题。

DESCRIPTION (provided by applicant): 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 Bordetella 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.