Global and temporal effects of virulence gene expression during pneumonic plague

描述（由申请方提供）：鼠疫耶尔森氏菌是毁灭性疾病鼠疫的病因，由于其传播潜力增加、疾病进展迅速以及发病率和死亡率高（特别是通过气溶胶途径），被列为A类选择因子。当个体吸入携带Y的气溶胶或飞沫时会导致原发性肺鼠疫。鼠疫，因此具有高度传染性，几乎总是致命的。小鼠感染模型显示，原发性肺鼠疫是一种令人惊讶的双相综合征，其中感染在最初的24-36小时内以静止或抗炎状态开始，随后在48小时内转变为高度促炎状态。因此，为了生存，复制，并被传送到新的主机，Y。鼠疫必须能够控制和应对迅速变化的宿主环境。在感染期间耶尔森氏菌毒力的必要组分是基于质粒的YscType III分泌系统（T3 SS），其将六种效应蛋白直接递送到宿主细胞的胞质溶胶中。这些被称为Yops的蛋白质一起被认为调节宿主反应以防止吞噬作用、炎症和激活针对耶尔森氏菌属物种的有效免疫，特别是在感染早期。由于要求的T3 SS鼠疫毒力在肺和差异的基因表达模式的效应Yops在感染过程中，我预测的相对贡献的Yops肺部感染的变化作为宿主细胞的类型和肺部的炎症状态被改变。因此，本研究的目标是：1）确定六种效应Yop中的每一种如何对Y的毒力做出贡献。鼠疫菌和改变宿主炎症状态在原发性肺鼠疫感染的小鼠模型中，通过有针对性地删除这些基因从完全强毒株，和2）检查细菌基因表达的时机如何影响Y.鼠疫杆菌，以通过使用外源诱导型启动子系统改变Yop表达来调节肺中抗炎状态和促炎状态之间的转变。在这样做的过程中，我期望能更好地理解Y。鼠疫能够成功地感染肺部并致病，这将有助于确定疫苗开发和治疗这一公共卫生威胁的目标。

DESCRIPTION (provided by applicant): Yersinia pestis, the cause of the devastating disease plague, is classified as a Category A select agent due to its elevated potential for transmissibility, rapid disease progression, and high morbidity and mortality, particularly by the aerosol route. Primary pneumonic plague results when an individual inhales aerosols or droplets carrying Y. pestis, and as such is highly contagious and almost always fatal. A mouse model of infection shows that primary pneumonic plague is a surprisingly biphasic syndrome, in which the infection begins with a quiescent or anti-inflammatory state in the first 24-36 hours that subsequently transitions to a highly pro-inflammatory state by 48 hours. Thus, in order to survive, replicate, and be transmitted to new hosts, Y. pestis must be able to control and respond to a rapidly changing host environment. A necessary component of Yersinia virulence during infection is the plasmid-based YscType III secretion system (T3SS) that delivers six effector proteins directly into the cytosol of host cells. Together these proteins, termed Yops, are thought to modulate the host response to prevent phagocytosis, inflammation, and activation of effective immunity against Yersinia species, particularly early in the infection. Due to the requirement of the T3SS to plague virulence in the lung and the differential gene expression pattern of the effector Yops during infection, I predict that the relative contributions of the Yops to the pulmonary infection change as the types of host cells and inflammatory state of the lungs are altered. Therefore, the goals of this study are 1) to determine how each of the six effector Yops contribute to the virulence of Y. pestis and changing host inflammatory state during primary pneumonic plague in the mouse model of infection via the targeted deletion of these genes from a fully virulent strain, and 2) to examine how the timing of bacterial gene expression affects the ability of Y. pestis to modulate the transition between the anti- and pro-inflammatory states in the lung by altering Yop expression using an exogenously inducible promoter system. In so doing, I anticipate developing a better understanding of how Y. pestis is able to successfully infect the lungs and cause disease, which will facilitate the identification of targets for vaccine development and treatment for this public health threat.