Dissecting Bubonic Plague

解剖黑死病

• 批准号: 8943726
• 负责人: VIRGINIA L MILLER
• 金额: $ 37.41万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8943726
• 关键词: Affect; Appearance; Arthropods; Bacteria; Biological Assay; Bioterrorism; Bite; Blood; Bubonic Plague; Cells; Cessation of life; Country; Data; Development; Disease; Disease Progression; Effectiveness; Emerging Communicable Diseases; Event; Fleas; Foundations; Goals; Human; Incidence; Infection; Infection Control; Intervention; Lead; Light; Lymphatic; Lymphatic System; Mammals; Modeling; Monitor; Mus; Nature; Oligonucleotides; Pathogenesis; Pathology; Phagocytes; Phenotype; Plague; Play; Population Dynamics; Property; Recording of previous events; Reporting; Role; Route; Site; Spleen; Systemic infection; Testing; Time; Tissues; Vaccines; Virulence; Virulence Factors; Virulent; Yersinia pestis; animal ecology; feeding; human ecology; insight; lymph nodes; macrophage; mortality; mutant; neutrophil; pandemic disease; pathogen; pathogenic bacteria; public health relevance; therapeutic target; trafficking; transmission process

 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.

 描述（由适用提供）：耶尔森氏菌是多种哺乳动物中疾病的灾难性药物，当人类和动物生态相交时，人类会被感染。这导致了人类历史上的几种大瘟疫大流行，而WHO目前将佩斯蒂斯感染视为重新出现的感染，因为许多国家发生了许多事件。泡沫瘟疫（通过跳蚤叮咬传播）是最常见的疾病形式，未经处理的死亡率估计为40-70％。小鼠是Pestis的天然宿主，长期以来一直用于研究Y. Pestis与哺乳动物在正常周期中的相互作用。这样的优点是我们可以使用充分的毒细菌和小型接种物。此外，Y. Pestis在遗传上是可探讨的，允许详细的分析。这些功能可用于获得对Y. Pestis-Host互动的更深入的了解，并且 同样，Y. Pestis成为理解节肢动物传播病原体需要克服的障碍的有用且非常敏感的模型。最近，我们完善了一个皮内感染模型（以更好地通过跳蚤进行模拟接种），并开发了一种传播测定法，使我们能够在很早的时间点监测人群动态。我们最近的结果表明，在排水淋巴结（DLN）中接种部位和建立感染之间存在很强的瓶颈，在运输到DLN或用于DLN或用于 瓶颈，细菌可以在淋巴细胞中作为游离细菌传播。这些观察结果导致了以下假设：运输到DLN不需要特定的细菌确定剂，而是在DLN中建立感染和/或从DLN到全身部位的传播所必需的。我们的长期目标是了解早期事件最终导致成功的系统感染和向新宿主传播。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和系统性定植的发展。这些研究共同使我们更清楚地了解了宿主 - 病原体相互作用和特定病毒决定者如何影响泡沫瘟疫的发展，从而为开发干预策略提供了基础。