Pulmonary infection by aerosol: pathogenesis and intervention

气溶胶肺部感染：发病机制和干预

• 批准号: 7669935
• 负责人: Gerard J Nau
• 金额: $ 30.87万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-03 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669935
• 关键词: Address; Aerosols; Bacteria; Biological; Bioterrorism; Burkholderia pseudomallei; Diagnosis; Disease; Equipment; Etiology; Francisella tularensis; Functional disorder; Gene Expression; Goals; Growth; Host resistance; Immune; Immune response; Immune system; Immunology; Immunotherapy; Individual; Infection; Intervention; Kinetics; Lethal Dose 50; Lung; Microbiology; Morbidity - disease rate; Mus; Natural History; Organism; Outcome Measure; Pathogenesis; Production; Research; Research Infrastructure; Resistance; Respiratory Tract Infections; Route; Therapeutic Intervention; Training; Work; Yersinia pestis; aerosolized; base; biodefense; cytokine; gene therapy; in vivo; interleukin-12 subunit p40; interleukin-23; microbial; mortality; pathogen; programs; research study; success; therapy development

Aerosolization is the most dangerous route of infection by select agents. Because of difficulty in diagnosis, it would be valuable to have therapies active against a broad range of aerosolized pathogens. Remarkably, ittle is known about the pathophysiology, microbiology, and immunology associated with aerosol delivery. This is due mostly to infrastructure requirements for aerosolization experiments, the specialized equipment that is necessary, and the limited number of individuals trained in the field of aerobiology. The work proposed in this application addresses this lack of understanding by combining expertise in aerobiology, microbial pathogenesis, immunology, and gene therapy. The ultimate goal of this program is to identify commonalities or deficiencies in host responses that can be targeted by immunotherapies, treatments that would benefit an individual exposed to any number of bioterrorism agents. To address this, three different select agent bacterial pathogens have been chosen for detailed study: Francisella tularensis, Yersinia pestis, and Burkholderia pseudomallei. Each of these pathogens alters host responses, thereby enhancing their success against the host. Bolstering host responses, therefore, is an attractive strategy to mitigate morbidity and mortality by agents like these three pathogens, regardless of the actual bacterium infecting the host. To identify immunotherapies providing cross-pathogen protection against aerosol infection, we propose these specific aims: Aim 1: To characterize the natural history of bacterial select agents delivered by aerosol. The objective of this aim is to characterize the pathophysiology of the three bacterial pathogens aerosolized into mice. Aim 2: To determine shared and distinct innate and bridging immune responses to bacterial select agents. These studies will characterize the innate and bridging immune response to F. tularensis, B. pseudomallei, and Y. pestis. Aim 3: To manipulate early host responses as therapeutic interventions. These studies will investigate whether augmenting innate and/or bridging immune responses with Th1 or Th17 effector cytokines can bolster host resistance to F. tularensis, B. pseudomallei, and Y. pestis delivered as an aerosol.

气化是特定药物最危险的感染途径。由于诊断困难 在广泛的雾化病原体上，将疗法活跃起来将是有价值的。值得注意的是 关于与气溶胶递送相关的病理生理学，微生物学和免疫学知之甚少。 这主要是由于气化实验的基础设施要求，专用设备 这是必不可少的，并且在有机生物学领域受过培训的个人数量有限。工作 在本申请中提出的提议通过结合有机生物学专业知识来解决这种缺乏理解， 微生物发病机理，免疫学和基因治疗。该计划的最终目标是确定 宿主反应中可以通过免疫疗法来针对的宿主反应中的共同点或缺陷 将使暴露于任何数量的生物恐怖剂的人受益。为了解决这个问题，三个不同 精选剂细菌病原体已被选择用于详细研究：弗朗西斯菌tularensis，耶尔森尼亚鼠疫， 和Burkholderia pseudomallei。这些病原体中的每一个都改变了宿主的反应，从而增强了他们的 对主持人的成功。因此，加强宿主的反应是减轻发病率的有吸引力的策略 和这样的三种病原体的药物的死亡率，无论实际感染宿主的实际细菌。到 确定提供针对气溶胶感染的交叉病原体保护的免疫疗法，我们提出 具体目的：目标1：表征气溶胶传递的细菌选择剂的自然史。 该目的的目的是表征三种细菌病原体的病理生理学 进入老鼠。目标2：确定对细菌的共享和独特的先天和桥接免疫反应 选择代理。这些研究将表征对F. tularensis的先天和桥接免疫反应。 假单胞菌和Y. Pestis。目标3：操纵早期宿主反应作为治疗干预措施。 这些研究将调查是否增加与TH1或TH1或 Th17效应细胞因子可以增强对F. tularensis，B。pseudomallei和Y. Pestis的抗宿主的抗性 作为气溶胶。