Mediators and inhibitors of immunity to Yersinia pestis

鼠疫耶尔森菌免疫介质和抑制剂

• 批准号: 7642990
• 负责人: Jon D. Goguen
• 金额: $ 38.63万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642990
• 关键词: Address; Adoptive Transfer; Aerosols; Alternative Therapies; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antibodies; Antigen Presentation; Antigens; Area; B-Lymphocytes; Bacteria; Biological; Biological Assay; Biological Warfare; Breathing; Cataloging; Catalogs; Categories; Cells; Cellular Immunity; Clinical Trials; Collaborations; Development; Disease; Drug Formulations; Elements; Engineering; Environment; Escherichia coli; Facility Construction Funding Category; Genomics; Goals; Homologous Gene; Hour; Human; Humoral Immunities; Hybrids; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Individual; Infection; Institution; Interleukin-10; Knockout Mice; Libraries; Licensing; Liver; Location; Lung; Macrophage Activation; Mediator of activation protein; Modeling; Molecular Weight; Mouse Strains; Mus; Numbers; Organism; Persons; Phylogenetic Analysis; Plague; Play; Pneumonic Plague; Primates; Production; Property; Protein Array; Protein Array Analysis; Proteins; Proteomics; Pseudomonas aeruginosa; Research Personnel; Resistance; Role; Route; Salmonella; Screening procedure; Spleen; Subcutaneous Injections; Symptoms; T-Lymphocyte; TLR2 gene; Techniques; Technology; Terrorism; Testing; Therapeutic; Therapeutic immunosuppression; Thinking; Time; Type III Secretion System Pathway; Vaccines; Virulence; Work; Yersinia; Yersinia enterocolitica; Yersinia pestis; Yersinia pestis V antigen; animal tissue; base; combinatorial; cytotoxicity; extracellular; flu; high throughput screening; immune function; inhibitor/antagonist; killings; macrophage; mutant; novel; novel vaccines; research study; response; small molecule; small molecule libraries; tissue culture; tool; transmission process; vaccine development

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.

鼠疫耶尔森氏菌是鼠疫的病原体，具有很高的用作生物武器的潜力， 战争恐怖主义，并被列为A类代理。其有效的人与人之间的传输， 气溶胶途径，原发性肺鼠疫的快速致命过程，非常快速的必要性， 抗生素治疗机构和缺乏有效的疫苗是主要关切问题。这个项目 三大目标：建立有助于对肺炎免疫的基本机制 感染Y.鼠疫;确定是否间接涉及免疫抑制活性， 其他耶尔森氏菌的毒力在鼠疫中起重要作用;以及小分子抑制剂的发现， Y.增强鼠疫毒力的功能。这些抑制剂将作为开发非抗生素的基础。 可能用于治疗抗生素耐药Y.鼠疫，或用于延长 抗生素治疗可能有效的窗口。本建议书中要执行的工作将是 这是一项由几名在相关领域具有专门知识的调查人员参与的合作。具体来说，我们将比较 通过各种途径（包括真气雾剂和 （与哈代Kornfeld博士合作，UMMS）和鼻内感染，以确定最合适的 用于后续实验的模型。这些发现将应用于针对以下方面的研究： 表征对Y的免疫应答所需的要素。鼠疫此外，我们将建立和 分析基因改变的Y染色体LcrV/TLR-2相互作用缺陷的鼠疫菌株被认为发挥了作用， 在免疫抑制中的重要作用（与UMMS的Egil Lien博士一起），设计高通量测定法， 筛选III型分泌和LcrV/TLR-2相互作用的低分子量抑制剂。埃吉尔博士 UMMS的Lien与UMMS的Shan Lu博士合作，将测试在 免疫学分析作为预防肺鼠疫疫苗组分的潜在效用。 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BSL 3动物和组织培养核心。