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（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，人类就会被感染，这导致了人类历史上的几次鼠疫大流行和耶尔森氏菌感染。鼠疫目前被世界卫生组织视为一种重新出现的传染病，因为黑死病（通过跳蚤叮咬传播）是最常见的疾病形式，因此在许多国家发病率有所增加。未经处理的死亡率估计为 40-70%，小鼠是鼠疫耶尔森氏菌的天然宿主，长期以来一直被用来研究鼠疫耶尔森氏菌在正常周期内与哺乳动物的相互作用。细菌和小接种物；此外，鼠疫耶尔森氏菌在遗传上易于处理，因此可以进行详细分析，这有助于更全面地了解鼠疫耶尔森氏菌与宿主的相互作用。 也使鼠疫耶尔森氏菌成为了解节肢动物传播的病原体需要克服的障碍的有用且非常敏感的模型。我们最近改进了皮内感染模型（以更好地模拟通过跳蚤的接种），并且还开发了一种传播测定法，使我们能够监测。我们最近的结果表明，在接种部位和引流淋巴结（dLN）中感染的建立之间存在很大的瓶颈，中性粒细胞也不需要运输到淋巴结。 dLN 或用于 瓶颈，并且细菌可以作为游离细菌在淋巴管中传播。这些观察结果得出这样的假设：特定的细菌决定簇不是运输到 dLN 所必需的，而是在 dLN 中建立感染和/或从 dLN 传播所必需的。我们的长期目标是了解最终导致成功的全身感染并传播到新宿主的早期事件，具体来说，我们建议确定已知的毒力因子如何影响接种之间的特定步骤。以及关键宿主细胞如何影响病理学和全身定植的发展，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黑死病的发展，为干预措施的发展提供基础。策略。