Dissecting Bubonic Plague

 描述（由申请人提供）：鼠疫耶尔森氏菌是多种哺乳动物疾病的病原体，当人类和动物生态相交时，人类可能被感染。这导致了人类历史上的几次鼠疫大流行，感染Y。由于鼠疫在许多国家的发病率增加，世界卫生组织目前认为鼠疫是一种重新出现的传染病。腺鼠疫（通过跳蚤叮咬传播）是最常见的疾病形式，未经治疗的死亡率估计为40 - 70%。小鼠是Y.鼠疫菌，长期以来一直被用于研究Y.在正常的周期里感染哺乳动物这种方法的优点是可以使用全毒力的细菌和少量的接种物;鼠疫在遗传学上易于控制，可以进行详细分析。这些特征有助于更全面地了解Y。害虫与宿主的相互作用， 也使Y。鼠疫是了解节肢动物传播的病原体需要克服的障碍的有用和非常敏感的模型。我们最近改进了一种皮内感染模型（以更好地模拟通过跳蚤接种），并开发了一种传播试验，使我们能够在很早的时间点监测种群动态。我们最近的研究结果表明，在引流淋巴结（dLN）的接种部位和感染建立之间存在一个很强的瓶颈，即中性粒细胞不需要运输到dLN，也不需要运输到淋巴结。 瓶颈，并且细菌可以作为游离细菌在消化道中传播。这些观察结果导致了这样的假设，即特定的细菌决定簇不需要运输到dLN，但需要建立感染的dLN和/或从dLN传播到全身部位。我们的长期目标是了解最终导致成功全身感染并传播到新宿主的早期事件。具体而言，我们建议确定已知的毒力因子如何影响接种部位和血液之间的特定步骤，以及关键宿主细胞如何影响病理学和系统性定植的发展。这些研究将使我们更清楚地了解宿主-病原体相互作用和特定毒力决定因素如何影响腺鼠疫的发展，为制定干预策略提供基础。

 DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of disease in a variety of mammals, and humans can become infected when human and animal ecologies intersect. This has led to several pandemics of plague in human history, and infection with Y. pestis is currently considered by the WHO as a re-emerging infectious disease because of the increased incidence in a wide number of countries. Bubonic plague (transmitted via flea bite) is the most common form of disease and the untreated mortality rate is estimated at 40-70%. Mice are a natural host for Y. pestis and have long been used to study interactions of Y. pestis with a mammal during its normal cycle. Advantages of this are that we can use fully virulent bacteria and small inocula; furthermore, Y. pestis is genetically tractable allowing detailed analyses. These features are useful for gaining a fuller understanding of Y. pestis-host interactions, and it also make Y. pestis a useful and very sensitive model for understanding the hurdles an arthropod borne pathogen needs to overcome. We recently refined an intradermal infection model (to better mimic inoculation via a flea) and also developed a dissemination assay that allows us to monitor population dynamics at very early time points. Our recent results indicate there is a strong bottleneck between the inoculation site and establishment of infection in the draining lymph node (dLN), that neutrophils are not needed either for trafficking to the dLN or for the bottleneck, and that the bacteria can disseminate as free bacteria in the lymphatics. These observations lead to the hypothesis that specific bacterial determinants are not required for trafficking to the dLN but are required for establishing infection in the dLN and/or dissemination from the dLN to systemic sites. Our long-term goal is to understand the early events ultimately leading to a successful systemic infection and transmission to a new host. Specifically we propose to determine how known virulence factors affect specific steps between the inoculation site and blood, and how key host cells affect the development of pathology and systemic colonization. Together these studies will give us a clearer picture of how host-pathogen interactions and specific virulence determinants affect development of bubonic plague, providing a foundation for development of intervention strategies.