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共栖物/病原体中出现的事件对我们应对其日益频繁的爆发的能力非常重要。在一项有趣的自然实验中，广泛的动物之间持续的共生，支气管脓毒杆菌，独立地产生了两种密切相关的人类病原体，百日咳双球菌和副百日咳双球菌。这两种微生物都具有高度传染性，引起具有高病理学的急性疾病，并对抗体介导的清除表现出强烈的抵抗力，这些特征在它们的共同祖细胞中没有观察到。我们最近的研究表明，百日咳使用百日咳毒素（PTx）来避免抗体介导的快速清除，使这种有机体感染免疫宿主；百日咳的典型特征。矛盾的是，百日咳双歧杆菌在同一宿主中引起相同的疾病，并且含有PTx基因但不表达它们。关于病毒向感染人类的能力明显趋同进化的历史观点无法解释这一点。博德特菌的另一个悖论是，这两种关系非常密切的生物在同一宿主种群中存在，并取得了显著的成功。进化理论预测，这两种密切相关的生物应该通过宿主群体中免疫介导的压力来竞争。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外，博德特拉菌的进化在很大程度上是由居住在同一宿主种群的菌株之间的免疫介导竞争形成的。这个模型符合观察结果，即支杆菌感染我们周围的所有动物，但很少感染人类，而且通常是那些有免疫缺陷的人。我们的初步数据表明，结核分枝杆菌确实对免疫交叉保护敏感，并迅速从百日咳免疫动物中消灭。因此，从大多数健康人身上排除结核分枝杆菌是高水平百日咳免疫的结果。然而，百日咳双歧杆菌和副百日咳双歧杆菌都与支气管脓杆菌密切相关，在同一人群中共存，通常是同时存在的。在这里，我们提出了一个中心假设，即免疫介导的竞争塑造了博德tellae的进化，并且，通过扩展，百日咳B.和百日咳B.在失去交叉反应性抗原的强烈选择压力下。我们使用我们的实验感染模型来直接检测交叉免疫和交叉反应抗原表达的影响。我们还扩展了已发表的基于MLST的系统发育，以检查来自人类和动物的密切相关的博德泰拉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部和宿主之间动态模型

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.