Emerging understanding of the rat flea response to Yersinia pestis infection

项目摘要 跳蚤是专性吸血节肢动物，与几种著名的细菌衍生的人类 疾病，即立克次体病、巴尔通体病和鼠疫。由革兰氏阴性菌耶尔森氏菌引起的鼠疫 鼠疫难以根除，因为蚤媒传播在野生啮齿动物的自然疫源地流行， 全球范围内的跳蚤。免疫控制是疾病管理的主要策略，但与许多疾病一样， 病媒传播的疾病由于跳蚤对杀虫剂产生抗药性而受到损害。发展 因此，用于细菌病原体控制的新的基于载体的策略是优先考虑的。然而，要做到这一点， 我们必须克服跳蚤生物学知识的缺乏，特别是跳蚤的详细过程， 宿主对感染的反应。为了实现这一目标，我们的实验室最近进行了新的观察，Y。鼠疫 因子Ymt参与操纵与血红素解毒有关的血粉消化过程， 血液来源依赖性。我们的目标是了解Ymt介导的跳蚤对感染的反应， 成功的Y。鼠蚤的鼠疫感染。因此，我们的中心假设是Ymt调节小鼠 与血红素解毒和抗氧化防御有关的血液消化过程，使Y。鼠疫感染 鼠蚤两个目标将检验这一假设。在目标1中，我们将确定血粉来源的血红素是否与 跳蚤ROS介导的免疫应答以Ymt和血液来源依赖的方式存在。在目标2中，我们将使用 比较转录组学以鉴定以Ymt特异性方式调节的跳蚤转录物。我们 拟议的探索性研究有可能揭示与血液消化有关的生物过程， 跳蚤媒介中的免疫过程，可以有针对性地减少传染性感染的建立， 人类因此，拟议的研究属于NIH的使命的一部分，即开发基本的 有助于减轻传染病对人类健康负担的知识。

PROJECT SUMMARY Fleas are obligate blood-feeding arthropods that are associated with several notable bacterial-derived human diseases, i.e. rickettsioses, bartonelloses, and plague. Plague caused by the Gram negative bacterium, Yersinia pestis, is difficult to eradicate because flea-borne transmission is endemic in natural foci of wild rodents and their associated fleas world-wide. Insecticide control is the primary strategy for disease management, but like many vector-borne diseases this is compromised by development of insecticide resistance in fleas. Development of novel vector-based strategies for bacterial pathogen control are therefore a priority. However, to accomplish this, we must overcome the dearth in knowledge regarding flea biology, particularly the detailed processes of the flea host response to infection. Towards this goal our lab has recently made novel observations that the Y. pestis factor Ymt is involved in manipulating the bloodmeal digestion processes related to detoxification of heme in a blood source dependent manner. Our goals are to understand the Ymt-mediated flea responses to infection that underlie successful Y. pestis infection of rat fleas. Therefore, our central hypothesis is that Ymt modulates mouse blood digestion processes related to heme detoxification and antioxidant defense to enable Y. pestis infection in rat fleas. Two aims will test this hypothesis. In Aim 1 we will determine if bloodmeal derived heme is correlated with flea ROS-mediated immune responses in a Ymt and blood source dependent manner. In Aim 2 we will use comparative transcriptomics to identify flea transcripts that are modulated in a Ymt-specific manner. Our proposed exploratory studies have potential to uncover biological processes related to blood digestion and immune processes in flea vectors that can be targeted to reduce establishment of transmissible infections to humans. Therefore, the proposed research lies within a part of the NIH's mission to develop fundamental knowledge that will assist in reducing the burden of infectious diseases on human health.