Non-invasive Optical Imaging of Select Agent Bacteria in Non-human Primates

非人类灵长类动物中选择性细菌的非侵入性光学成像

• 批准号: 7914370
• 负责人: Don MARK ESTES
• 金额: $ 44.88万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914370
• 关键词: Abscess; Acute; Aerosols; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Bacteria; Bacteriology; Biological Warfare; Bioterrorism; Burkholderia mallei; Burkholderia pseudomallei; Callithrix; Characteristics; Clinical; Clinical Pathology; Collaborations; Communicable Diseases; Complement; Containment; Cutaneous; Data; Development; Diagnostic; Disease; Disease Progression; Disease model; Event; Funding; Future Generations; Generations; Genetic; Glanders; Human; Image; Imaging Techniques; Imaging technology; Immune response; Immunocompromised Host; Immunology; Individual; Infection; Ingestion; Intervention; Licensing; Lung; Melioidosis; Metabolic; Microarray Analysis; Mind; Modeling; Mus; National Institute of Allergy and Infectious Disease; Opportunistic Infections; Organism; Pathogenesis; Pattern; Pharmaceutical Preparations; Phase; Play; Population; Public Health; Regimen; Relapse; Reporter; Research; Research Personnel; Role; Safety; Site; System; Therapeutic Uses; Time; Tissues; Treatment Failure; Tularemia; Vaccines; Whole Blood; Work; biodefense; cohort; cost; diabetic; disorder control; follow-up; genome-wide; imaging modality; improved; mortality; nonhuman primate; novel strategies; optical imaging; pathogen; peripheral blood; preclinical study; programs; prophylactic; research study; respiratory; response; weapons

There is an urgent need to develop more effective vaccines and antibiotic regimens against many of the Select Agent bacteria that cause lethal infection in humans. This is particularly true for the candidate bioterrorism agents, Burkholderia. pseudomallei (Bp) and Burkholderia mallei (Bm), the causative agents of human melioidosis and glanders. These Gram negative, facultative intracellular pathogens share many common features of their genetics, pathogenesis, host immune response and clinical pathology. B. mallei primarily infect solipeds but the disease is transmissible to humans by ingestion and cutaneous or aerosol exposures. Concern over this bacterium and the very closely related species B. pseudomallei has heightened because of the pathogens' seemingly perfect characteristics for malevolent uses as bioterror or biowarfare weapons against both animals and humans. In modern times their potential destructive impact on public health has escalated due to the pathogens' opportunistic infection of diabetic and immunocompromised people, two growing populations worldwide. For both pathogens, severe infection in humans carries a high mortality rate, all are recalcitrant to antibiotic therapy and no licensed vaccine exists for either prophylactic or therapeutic use. Small animal models of infectious disease play a central role in research programs aimed at identifying leads and approaches that could be exploited to devise improved diagnostics, pre-treatments and therapies against bioterrorism agents. However, the further development of promising leads is dependent on additional animal models of infection which more faithfully represent humans. It is clear that the large body of high quality biodefense research currently funded by NIAID will identify promising new approaches to disease control, and that the development of these approaches will be dependent on reliable, reproducible and relevant models of infection. With this in mind we propose a UO1 project to develop non-human primate models of melioidosis and glanders which allow the direct optical imaging of the infection. This work builds on our current NIAID projects to devise non-human primate models of tularaemia and melioidosis. The ability to image the infection will provide a significant advantage over more conventional non-human primate models of disease, because it allows additional data on the temporal and spatial pattern of the infection to be gathered from each animal. In addition, we believe it will be possible to gather data on the metabolic status of the bacteria in tissues. The additional data acquired by optical imaging of the infection will have benefits in providing additional information to support preclinical studies and advancement of products into phase I clinical safety trials in humans. Also, the ability to acquire additional data from each animal could reduce the overall numbers of animal used in these programmes, for example by providing multiple time point data from a single animal. We believe that the development of sensitive, non-invasive imaging techniques which can be applied to non human primates is an essential step in the generation of future clinical interventions to Select Agent bacteria. The purpose of this application is to apply recent advances in whole animal bioluminescent and fluorescent imaging to study the pathogenesis and treatment of melioidosis and glanders in marmosets. This will be complemented by genome-wide transcriptional microarray analysis of whole blood from infected animals to provide an in-depth view of the immunological response to infection. Given the high cost and logistical constraints of non-human primate studies conducted in containment, combining these non- lethal analytical approaches will provide a comprehensive picture of the dynamics of infection and response to treatment, while reducing the number of animals needed for each study. PHS 398/2650 (Rev. 11/07) Page 12 Continuation Format Page

迫切需要针对许多引起人类致命感染的精选剂细菌开发更有效的疫苗和抗生素方案。对于候选生物恐怖主义者Burkholderia而言，尤其如此。假单胞菌（BP）和Burkholderia Mallei（BM），人类黑麦片和腺体的病因。这些革兰氏阴性，辅助细胞内病原体具有其遗传学，发病机理，宿主免疫反应和临床病理的许多常见特征。 B. mallei主要感染溶剂，但通过摄入，皮肤或气溶胶暴露，该疾病可以传播到人类。由于病原体看似完美的特征，即对动物和人类的生物植物或生物质量武器，因此对这种细菌和密切相关的物种的关注点了。在现代，由于病原体对糖尿病和免疫功能低下的人的机会性感染，他们对公共卫生的潜在破坏性影响不断升级，这是全球两个人口增长。对于两种病原体，人类的严重感染均具有较高的死亡率，所有病原体都是抗生素治疗的顽固性，并且不存在用于预防性或治疗用途的许可疫苗。传染病的小动物模型在研究计划中起着核心作用，旨在确定可以利用的潜在客户和方法来设计改善针对生物恐怖剂的诊断，治疗和疗法。但是，有前途的潜在客户的进一步发展取决于其他更忠实地代表人类的感染模型。显然，当前由NIAID资助的大量高质量生物探索研究将确定有希望的新方法来控制疾病，这些方法的发展将取决于可靠，可重复的和相关的感染模型。考虑到这一点，我们提出了一个UO1项目，以开发非人类的灵长类动物模型和腺体，以直接对感染进行光学成像。这项工作以我们目前的NIAID项目为基础，旨在设计非人类的灵长类动物学模型和Melioidosis。与更常规的非人类灵长类动物模型相比，对感染进行成像的能力将提供显着优势，因为它允许从每只动物中收集有关感染的时间和空间模式的其他数据。此外，我们认为可以收集有关组织中细菌代谢状况的数据。通过光学成像对感染获得的附加数据将在提供其他信息以支持临床前研究和将产品发展为I期临床安全试验中的其他信息。同样，从每种动物中获取其他数据的能力可以减少这些程序中使用的动物的总数，例如，通过提供单个动物的多个时间点数据。我们认为，可以应用于非人类灵长类动物的敏感，非侵入性成像技术的发展是未来临床干预措施以选择剂菌细菌的重要一步。该应用的目的是应用全动物生物发光和荧光成像中的最新进展来研究果果中黑酚和腺体的发病机理和治疗。全基因组的转录微阵列分析对感染动物的全血的分析将得到补充，以提供对感染的免疫学反应的深入观察。鉴于在遏制中进行的非人类灵长类动物研究的高成本和后勤限制，将这些非致命的分析方法结合起来将为感染动力和对治疗的反应提供全面的了解，同时减少每项研究所需的动物数量。 PHS 398/2650（Rev. 11/07） 第12页 延续格式页面