Host response to Yersinia pestis infection

描述（由申请方提供）：鼠疫耶尔森氏菌是一种偶然的人类病原体，是鼠疫的病原体。历史上，鼠疫一直是人类发病率和死亡率的重要来源。在鼠疫在啮齿动物种群中流行的地区，人类仍然面临重大风险。鼠疫可能重新出现，对人类健康构成重大威胁，因为最近发现了耐多药的耶尔森氏菌菌株。鼠疫和Y.鼠疫可能被用作生物恐怖主义的一种制剂。虽然鼠疫已经成为一个主要的健康问题超过1500年，相对没有什么是知道的发病机制的Y。鼠疫感染特别是，详细的分子数据的主机响应Y。没有鼠疫感染。这些数据对于开发新的治疗方法至关重要，并可能显着改善疫苗策略。利用Y.小肠结肠炎菌感染与感染组织的微阵列分析相结合，我们已经获得了对宿主对致病性耶尔森氏菌的应答的显著了解。这些研究提高了我们对宿主对Y.小肠结肠炎菌，并应作为一个模板的宿主反应分析Y。鼠疫根据我们以前的调查，我们假设：Y。鼠疫感染诱导编码免疫调节蛋白（细胞因子、趋化因子、蛋白酶和免疫效应物）的基因的表达，并且这些蛋白的表达决定感染的结果。为了验证这些假设，我们提出：1）全面分析宿主基因表达对Y。2）分析确定的宿主缺陷对鼠疫菌免疫应答的影响。体内鼠疫感染。我们将利用来自Y.鼠疫感染的小鼠，包括确定的（细胞因子）宿主突变体，以研究宿主对鼠疫的反应。此外，将使用小鼠感染模型检查细胞因子（TARC、TGF-β、TNF-α、IL-13、IL-6、IL-10）的作用。这些研究将提高我们对宿主对Y.鼠疫感染

DESCRIPTION (provided by applicant): Yersinia pestis is an incidental human pathogen that is the causative agent of plague. Historically plague has been a significant source of human morbidity and mortality. In areas where plague is endemic in rodent populations humans are still at significant risk. Plague may re-emerge as a significant danger to human health due to the recent identification of multi-drug resistant strains of Y. pestis and the possibility that Y. pestis may be used as an agent of biological terrorism. Although plague has been a major health problem for more than 1500 years, relatively nothing is known about the pathogenesis of Y. pestis infection. In particular, detailed molecular data on the host response to Y. pestis infection is lacking. This data is crucial for the development of new treatments and may significantly improve vaccine strategies. Using the mouse model of Y. enterocolitica infection combined with microarray analysis of infected tissues we have gained significant insight into the host response to the enteropathogenic Yersiniae. These studies have improved our understanding of the molecular basis of the host response to Y. enterocolitica and should serve as a template for an analysis of the host response to Y. pestis. Based on our previous investigations we hypothesize that: Y. pestis infection induces the expression of genes encoding immunomodulatory proteins (cytokines, chemokines, proteases, and immune effectors) and the expression of these proteins dictates the outcome of the infection. To test these hypotheses we propose: 1) A comprehensive analysis of host gene expression to Y. pestis infection 2) Analysis of the effect of defined host deficiencies on the immune response to Y. pestis infection in vivo. We will utilize microarray analysis of tissues from Y. pestis infected mice including defined (cytokines) host mutants to study the host response to plague. Additionally the roles of cytokines (TARC, TGF-beta, TNF-alpha, IL-13, IL-6, IL-10) will be examined using the mouse model of infection. These studies will improve our understanding of the host immune response to Y. pestis infection.