Host response to Yersinia pestis infection

描述(申请人提供)：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。从历史上看，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，人类仍面临重大风险。鼠疫可能会再次成为对人类健康的重大威胁，因为最近发现了鼠疫杆菌的多重耐药菌株，而且鼠疫杆菌可能被用作生物恐怖主义的媒介。尽管1500多年来，鼠疫一直是一个主要的健康问题，但相对来说，人们对鼠疫杆菌感染的发病机制知之甚少。特别是，关于宿主对鼠疫杆菌感染的反应的详细分子数据缺乏。这些数据对开发新的治疗方法至关重要，并可能显著改进疫苗策略。利用小肠结肠炎耶尔森氏菌感染的小鼠模型，结合感染组织的微阵列分析，我们对肠道致病性耶尔森氏菌的宿主反应有了重要的了解。这些研究提高了我们对宿主对小肠结肠炎耶尔森氏菌反应的分子基础的理解，并应作为分析宿主对鼠疫杆菌反应的模板。根据我们以前的研究，我们假设：鼠疫杆菌感染诱导了免疫调节蛋白(细胞因子、趋化因子、蛋白酶和免疫效应器)基因的表达，这些蛋白的表达决定了感染的结局。为了验证这些假说，我们提出：1)宿主基因表达对鼠疫杆菌感染的综合分析；2)体内宿主缺陷对鼠疫杆菌感染免疫应答的影响的分析。我们将利用微阵列分析鼠疫耶尔森氏菌感染小鼠的组织，包括明确的(细胞因子)宿主突变体，以研究宿主对鼠疫的反应。此外，细胞因子(TARC、转化生长因子-β、肿瘤坏死因子-α、白介素13、白介素6、白介素10)的作用将通过小鼠感染模型进行检验。这些研究将提高我们对宿主对鼠疫杆菌感染的免疫反应的了解。

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.