Factors Affecting Dissemination Events Early in Bubonic Plague

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，当人类和动物的生态系统相交时，人类可能会被感染。这导致了人类历史上几次鼠疫大流行，由于许多国家的发病率增加，感染鼠疫杆菌目前被世卫组织视为一种重新出现的传染病。腺鼠疫是最常见的疾病形式，未经治疗的死亡率估计为40%-70%。 最近来自几个小组的一些研究表明，鼠疫杆菌在感染早期主动引起免疫抑制。此外，最近的研究表明，接种后的非常早期的事件是决定感染结果的原因。腺鼠疫发病的最初步骤之一是病原体从接种部位(IS)传播到引流淋巴结(DLN)。长期以来，人们一直认为细菌是通过运输吞噬细胞传播到DLN的。然而，令人惊讶的是，几乎没有活体数据证明这一点。我们推测，鼠疫耶尔森氏菌通过与宿主固有反应的关键成分相互作用，积极影响这些早期传播事件。我们的长期目标是了解鼠疫杆菌从IS向DLN传播的机制。使用皮内接种路线(最接近于跳蚤的路线)接种和我们最近开发的传播分析，我们能够监测细菌从IS到DLN，然后到全身组织的转移。在这里，我们将在体内专门测试(A)被广泛认为的吞噬细胞对于鼠疫菌从IS向DLN传播的重要性，以及(B)已知的影响体外与吞噬细胞相互作用的鼠疫杆菌毒力因子对早期传播到DLN的影响。

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.