Factors Affecting Dissemination Events Early in Bubonic Plague

影响黑死病早期传播事件的因素

• 批准号: 8605167
• 负责人: VIRGINIA L MILLER
• 金额: $ 22.62万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605167
• 关键词: Aerosols; Affect; Antigens; Appearance; Arthropods; Bacteria; Belief; Biological Assay; Bioterrorism; Bite; Bubonic Plague; Cells; Cessation of life; Country; Data; Defect; Development; Disease; Disease Progression; Emerging Communicable Diseases; Event; Fleas; Flow Cytometry; Genes; Genetic; Goals; Human; Immunosuppression; In Vitro; Incidence; Infection; Infection Control; Lead; Lymphatic System; Mammals; Modeling; Monitor; Mutation; Nature; Oligonucleotides; Organism; Outcome; Pathogenesis; Patients; Phagocytes; Phagocytosis; Plague; Population; Process; Recording of previous events; Reporting; Route; Shapes; Site; Staging; Staining method; Stains; Surveys; Testing; Therapeutic; Time; Tissues; Type III Secretion System Pathway; Vaccines; Virulence; Virulence Factors; Yersinia pestis; animal ecology; base; capsule; cell type; extracellular; feeding; human ecology; in vivo; insight; lymph nodes; mortality; mutant; pandemic disease; pathogen; pathogenic bacteria; prophylactic; public health relevance; response; therapeutic target; trafficking

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 is the most common form of disease and the untreated mortality rate is estimated at 40-70%. A number of recent studies from several groups suggest that Y. pestis actively causes immunosuppression early during infection. Furthermore, recent studies have shown that very early events after inoculation are responsible for determining the outcome of infection. One of the first steps in the pathogenesis of bubonic plague is dissemination of the pathogen from the inoculation site (IS) to the draining lymph node (DLN). It has long been believed that the bacteria disseminate to the DLN by trafficking in phagocytic cells. However, there is strikingly little in vivo data demonstrating this. We hypothesize that Y. pestis actively influences these early dissemination events by interacting with key components of the host innate response. Our long-term goal is to understand the mechanism of dissemination of Y. pestis from the IS to the DLN. Using an intradermal route (the route that most closely mimics that of the flea) of inoculation and a dissemination assay we recently developed, we are able to monitor the transit of bacteria to the DLN from the IS, and subsequently to systemic tissues. Here, we will specifically test in vivo (a) the widely held belief that phagocytic cells are important for traffiking Y. pestis from the IS to the DLN, and (b) effects by the Y. pestis virulence factors known to affect interactions with phagocytic cells in vitro for their impact on early dissemination to the DLN.

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，人类可能被感染。这导致了人类历史上的几次鼠疫大流行，由于许多国家的发病率增加，鼠疫耶尔森氏菌感染目前被世界卫生组织认为是一种重新出现的传染病。黑死病是最常见的疾病，未经治疗的死亡率估计为 40-70%。 多个小组最近的许多研究表明，鼠疫耶尔森氏菌在感染早期会主动引起免疫抑制。此外，最近的研究表明，接种后的早期事件决定了感染的结果。黑死病发病机制的第一步是将病原体从接种部位 (IS) 传播到引流淋巴结 (DLN)。长期以来人们一直认为细菌通过吞噬细胞的运输传播到DLN。然而，证明这一点的体内数据却少得惊人。我们假设鼠疫耶尔森氏菌通过与宿主先天反应的关键组成部分相互作用，积极影响这些早期传播事件。我们的长期目标是了解鼠疫耶尔森氏菌从 IS 到 DLN 的传播机制。使用皮内接种途径（最接近跳蚤的途径）和我们最近开发的传播测定，我们能够监测细菌从 IS 到 DLN 的转移，以及随后到全身组织的转移。在这里，我们将专门在体内测试（a）广泛持有的观点，即吞噬细胞对于将鼠疫耶尔森氏菌从 IS 贩运到 DLN 很重要，以及（b）已知鼠疫耶尔森氏菌毒力因子的影响，已知会影响体外与吞噬细胞的相互作用，因为它们对早期传播到 DLN 的影响。