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: 8233341
• 负责人: Larry S. Schlesinger
• 金额: $ 60.46万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233341
• 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传染性病原体是那些人为传播的病原体， 气溶胶进入肺部，那里的免疫反应是独特的，主要是由免疫调节因子驱动的。 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。土拉热弗朗西丝菌（Francisella tularensis，Ft）是一种生物恐怖主义的靶向感染因子， 导致急性危及生命的疾病的病原体，特别是通过气溶胶传播时。的 介导宿主细胞对Ft的识别和应答的真核和微生物因子仍然不清楚 并且它们的定义将是合理开发新疗法和疫苗所必需的。这 RP9的竞争性更新将来自俄亥俄州的一组合作科学家团结在一起 威斯康星州医学院和辛辛那提大学的合作，重点关注分子发病机制 肺性土拉菌病基于最近发表的工作和初步数据，我们的中心假设是 Ft作为人类病原体的成功与其抑制和/或破坏重要元素的能力有关 在感染的早期阶段保护性的先天免疫反应。为了验证这个假设，我们将 1)进一步确定介导Ft进入、细胞内运输、抗微生物 反应和启动炎症程序的体外和体内; 2）构建，验证， 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/或破坏;和3）使用靶向遗传方法来鉴定新的Ft 毒力决定簇集中在细菌转录调节因子和Ft和宿主因子参与Fe 代谢，包括细菌氧化应激反应。这些研究将提供 重要的新见解宿主-病原体相互作用的最致命的Ft亚种，并将使用新的 感染的突变衍生物和相关模型系统。这RP将协同其人才 研究人员将自己置于最具竞争力的地位，使有关的基本发现， Ft的致病机制，并开始将这些发现转化为产品开发。