EMERGENCE OF HUMAN PATHOGENS IN THE GENUS BORDETELLA

了解人类病原体从动物病原体中出现所涉及的事件 对我们应对其日益频繁的爆发的能力至关重要。在一个有趣的实验中， 在自然界中，广泛动物的持久寄生虫，支气管败血波氏杆菌， 独立于两种密切相关的人类病原体，B。百日咳和B.副百日咳。这两种生物都是 高度传染性，引起具有高度病理学急性疾病，并对抗体介导的 清除，在其共同祖先中未观察到的特征。我们最近证明了B。 百日咳使用百日咳毒素（PTx）来避免快速抗体介导的清除，使这种生物体 感染免疫宿主; 2 B B的一个特征。百日咳。巧合的是，B。副百日咳导致 在相同宿主中的相同疾病，并且包含PTx的基因但不表达它们。历史观 对感染人类能力的明显趋同进化无法解释这一点。另一 这两个非常密切相关的人的存在和显著的成功，是博德特莱的悖论。 在同一个宿主种群中。进化论预测，两个如此密切相关的物种 生物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，我们提出，除了选择最佳的相互作用与他们的 宿主，博德特氏菌的进化在很大程度上是由免疫介导的竞争形成的， 在同一宿主种群中生存的菌株。该模型与B.支气管 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， 从B中删除。免疫百日咳的动物因此排除了B。支气管败血症从大多数健康 人类是高水平的B的结果。百日咳免疫但是B。百日咳和B.副百日咳， 都与B密切相关。支气管败血症，在同一人群中共存，通常在 同时还研究与讨论在这里，我们提出了一个中心假设，即免疫介导的竞争塑造了 Bordetellae和扩展到B。副百日咳和B.百日咳是在强大的选择压力下， 交叉反应性抗原的丢失。我们使用我们的实验感染模型直接检查交叉免疫性 以及交叉反应性抗原表达的影响。我们还扩展了我们发布的MLST基于 遗传学检查一个群体中的许多抗原基因的序列密切相关， 博德特氏菌从人类和动物中分离。我们的系统发育研究已经确定了 感染人类和动物。使用我们的454机器，我们将有效地测序整个基因组， 这些菌株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 将对这些重新出现的人类病原体的宿主内和宿主间动力学模型进行参数化。

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 antibodymediated 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 crossimmunity 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.