Host bacterial targets mediating immune suppression in pneumonic tularemia

宿主细菌靶标介导肺炎兔热病的免疫抑制

• 批准号: 8448670
• 负责人: Larry S. Schlesinger
• 金额: $ 60.84万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448670
• 关键词: Academic Medical Centers; Acute; Aerosols; Alveolar Macrophages; Alveolus; Animal Model; Animals; Antioxidants; Attenuated Vaccines; Bacillus anthracis; Bacteria; Biochemical; Biological; Biological Assay; Biological Models; Biological Process; Biological Response Modifiers; Biology; Bioterrorism; Bite; Breathing; Categories; Cells; Cellular biology; Collaborations; Coupled; Cytosol; Data; Development; Disease; Elements; Environment; Enzymes; Epithelial Cells; Event; Francisella tularensis; Funding; Genetic; Genetic Screening; Genomics; Goals; Growth; Human; Immune; Immune response; Immunology; Immunosuppression; In Vitro; Infection; Infectious Agent; Inflammatory; Inflammatory Response; Integration Host Factors; Intervention; Iron; Life; Ligands; Link; Lung; Mammalian Cell; Mediating; Mediator of activation protein; Medicine; Metabolic Pathway; Metabolism; Microbe; Modeling; Molecular; Molecular Target; Mus; Natural Immunity; North America; Ohio; Oral; Oxidative Stress; Paper; Particulate; Pathogenesis; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Phase; Play; Pneumonia; Positioning Attribute; Printing; Process; Productivity; Property; Publishing; Reagent; Receptor Cell; Research; Research Personnel; Research Proposals; Respiratory Tract Infections; Rodent; Role; Route; Scientist; Severity of illness; Signal Transduction; System; Talents; Technology; Testing; Ticks; Translating; Tularemia; United States National Institutes of Health; Universities; Vaccine Therapy; Virulence; Virulent; Wisconsin; Work; Yersinia pestis; abstracting; aerosolized; antimicrobial; base; biodefense; biological adaptation to stress; biological systems; body system; college; cytotoxicity; experience; extracellular; in vivo; in vivo Model; insight; macrophage; man; medical schools; member; microbial; microbial host; mouse model; mutant; novel; novel diagnostics; novel strategies; pathogen; product development; programs; receptor; response; success; therapeutic vaccine; trafficking

The most worrisome infectious agents of bioterrorism are those that would be artificially disseminated as aerosols to the lungs where the immune responses are unique, primarily driven by an immunoregulatory program. Critical mediators of the immune response in this environment are alveolar macrophages (AM) and epithelial cells. Francisella tularensis (Ft), a targeted infectious agent of bioterrorism, is an intracellular pathogen which causes acute life-threatening disease, particularly when transmitted via aerosols. The eukaryotic and microbial factors mediating host cell recognition and response for Ft remain poorly defined and their definition will be required for the rational development of new therapies and vaccines. This competitive renewal of RP9 unites an established group of collaborative scientists from the Ohio State University, Medical College of Wisconsin and University of Cincinnati to focus on the molecular pathogenesis of pneumonic tularemia. Based on recently published work and preliminary data, our central hypothesis is that Ft's success as a human pathogen is linked to its ability to suppress and/or subvert important elements of the protective innate immune response during the early phase of infection. To test this hypothesis we will 1) further define the molecular mechanisms that mediate Ft entry, intracellular trafficking, antimicrobial responses and initiation of the inflammatory program both in vitro and in vivo; 2) construct, validate, and probe global microbial and host genetic screening platforms to identify key determinants mediating Ftinduced immune suppression and/or subversion; and 3) use targeted genetic approaches to identify novel Ft virulence determinants focusing on bacterial transcriptional regulators and Ft and host factors involved in Fe metabolism, including those of the bacterial oxidative stress response. Collectively, these studies will provide important new insights into host-pathogen interactions by the most virulent Ft subspecies, and will use novel mutant derivatives and relevant model systems of infection. This RP will synergize the talents of its investigators to place itself in the most competitive position to make fundamental discoveries related to pathogenic mechanisms for Ft, and begin to translate these discoveries into product development.

生物恐怖主义最令人担忧的感染源是那些会被人为传播为 肺部的气雾剂，免疫反应是独一无二的，主要由免疫调节驱动 程序。在这种环境中，免疫反应的关键介质是肺泡巨噬细胞(AM)。 和上皮细胞。图拉氏方济氏菌(Francisella tularsis，Ft)是生物恐怖主义的靶向感染源，是一种胞内致病因子。 引起危及生命的急性疾病的病原体，尤其是通过气雾剂传播时。这个 介导宿主细胞识别和应答Ft的真核和微生物因子仍未明确 它们的定义将是合理开发新疗法和疫苗所必需的。这 RP9的竞争性更新团结了来自俄亥俄州的一个既定的合作科学家小组 威斯康星大学医学院和辛辛那提大学关注分子发病机制 肺炎图拉热症。基于最近发表的研究和初步数据，我们的中心假设是 Ft作为人类病原体的成功与其抑制和/或颠覆重要元素的能力有关 在感染的早期阶段的保护性先天免疫反应。为了检验这一假设，我们将 1)进一步定义了介导Ft进入、细胞内转运、抗菌的分子机制 体外和体内炎症程序的反应和启动；2)构建、验证和 探索全球微生物和宿主遗传筛选平台，以确定介导Ft诱导的关键决定因素 免疫抑制和/或颠覆；以及3)使用有针对性的遗传方法来识别新的Ft 细菌转录调控因子、Ft因子和寄主因子参与Fe的毒力决定因素 新陈代谢，包括细菌的氧化应激反应。总的来说，这些研究将提供 毒力最强的Ft亚种对宿主-病原体相互作用的重要新见解，并将使用新的 突变的衍生物和相关的感染模型系统。这个RP将协同ITS的才能 调查人员将自己置于最具竞争力的位置，以做出与以下方面相关的根本发现 Ft的致病机制，并开始将这些发现转化为产品开发。