Mediators and inhibitors of immunity to Yersinia pestis

鼠疫耶尔森氏菌是鼠疫的病原体，在以下情况下具有用作生物武器的高潜力 战争恐怖主义，被归类为A类特工。其有效的人与人之间的传播通过 气雾剂路线，迅速致命的原发肺鼠疫，有必要非常迅速 抗生素治疗制度以及缺乏有效的疫苗是主要的关切。这个项目有 三大目标：建立促进肺炎免疫的基本机制 感染鼠疫杆菌；确定间接牵连的免疫抑制活动是否与 其他耶尔森氏菌的毒力在鼠疫中起着重要作用；而小分子抑制物的发现 鼠疫杆菌的毒力增强功能。这些抑制剂将成为开发非抗生素的基础。 可能对治疗耐药鼠疫杆菌有用的治疗方法，或用于延长 抗生素治疗可能有效的窗口。本提案中要执行的工作将是 几名在相关领域具有专业知识的调查人员参与的合作。具体地说，我们将比较 包括真气溶胶在内的各种途径对选定的小鼠品系的致病过程 (与UMMS Hardy Kornfeld博士合作)和鼻腔感染，以确定最合适的 在后续实验中使用的模型。这些发现将被应用于以下研究 描述对鼠疫杆菌的免疫反应所需的要素。此外，我们还将构建和 分析LcrV/TLR-2相互作用基因缺陷的鼠疫耶尔森菌 在免疫抑制方面发挥重要作用(与UMMS的Egil Lien博士一起)，设计高通量分析和 筛选III型分泌物和LcrV/TLR-2相互作用的低分子量抑制物。埃吉尔博士 UMMS的Lien与UMMS的陆山博士合作，将测试在 作为预防肺炎鼠疫疫苗成分潜在用途的免疫学分析。 该项目将大量使用拟议的NERCE核心，包括蛋白质组学、小分子筛选、 生物分子生产和BSL3动物和组织培养核心。

Yersinia pestis, the causative agent of plague, has high potential for use as biological weapon in the context of terrorism of warfare, and is classified as a category A agent. Its efficient person-to-person transmission via the aerosol route, the rapidly fatal course of primary pneumonic plague, the necessity for very rapid institution of antibiotic therapy, and the lack of an effective vaccine are major concerns. This project has three major goals: establishing the fundamental mechanisms that contribute to immunity against pneumonic infection with Y. pestis; determining if immunosuppressive activities that have been indirectly implicated in virulence of other yersiniae play a significant role in plague; and the discovery of small molecule inhibitors of Y. pestis virulence-enhancing functions. These inhibitors will serve as the basis for development on nonantibiotic therapeutics that may be useful in treatment of antibiotic-resistant Y. pestis, or used to extend the window in which antibiotic treatment may be efficacious. The work to be performed in this proposal will be a collaboration engaging several investigators with expertise in related areas. Specifically, we will compare the course of disease in selected mouse strains challenged by various routes including both true aerosol (collaboration with Dr. Hardy Kornfeld, UMMS) and intranasal infection to determine the most suitable models for use in subsequent experiments. These findings will be applied to studies directed towards characterizing the required elements of an immune response to Y. pestis. Additionally, we will construct and analyze genetically altered Y. pestis strains deficient in the LcrV/TLR-2 interaction thought to play an important role in immunosuppression (with Dr.Egil Lien at UMMS), devise high throughput assays and screen for low molecular weight inhibitors of type III secretion and the LcrV/TLR-2 interaction. Dr. Egil Lien at UMMS, in collaboration with Dr. Shan Lu at UMMS, will test novel antigens discovered in the immunological analysis for potential utility as vaccine components for protection against pneumonic plague. This project will heavily use proposed NERCE Cores including Proteomics, Small Molecule Screening, Biological Molecule Production, and BSL3 Animal and Tissue Culture Cores.