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: 7645250
• 负责人: Don MARK ESTES
• 金额: $ 144.7万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645250
• 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; Relapse; Reporter; Research; Research Personnel; Role; Safety; Site; System; Therapeutic Uses; Time; Tissues; Treatment Failure; Treatment Protocols; 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

迫切需要开发针对许多在人类中引起致命感染的选择代理细菌的更有效的疫苗和抗生素方案。对于候选生物恐怖主义制剂伯克霍尔德氏菌来说尤其如此。类鼻疽杆菌（Bp）和鼻疽伯克霍尔德菌（Bm），它们是人类类鼻疽病和鼻疽的病原体。这些革兰氏阴性、兼性胞内病原体在遗传学、发病机制、宿主免疫应答和临床病理学方面具有许多共同特征。B。鼻疽主要感染单足动物，但该疾病可通过摄入和皮肤或气溶胶接触传播给人类。关注这种细菌和非常密切相关的物种B。假鼻疽的发病率上升，是因为这种病原体似乎具有完美的特性，可用于针对动物和人类的生物恐怖或生物战武器。在现代，由于病原体对糖尿病和免疫功能低下人群的机会性感染，它们对公共卫生的潜在破坏性影响已经升级，这两个人群在世界范围内不断增长。对于这两种病原体，人类的严重感染具有高死亡率，所有病原体都对抗生素治疗无效，并且不存在用于预防或治疗用途的许可疫苗。传染病的小动物模型在研究方案中发挥着核心作用，这些研究方案旨在确定可用于设计针对生物恐怖主义制剂的改进诊断、预处理和疗法的线索和方法。然而，有希望的线索的进一步开发依赖于更忠实地代表人类的其他感染动物模型。很明显，目前由NIAID资助的大量高质量生物防御研究将确定有前途的疾病控制新方法，这些方法的发展将取决于可靠的，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UO 1项目，以开发非人类灵长类动物模型的类鼻疽和鼻疽，使直接光学成像的感染。这项工作建立在我们目前的NIAID项目，以设计非人灵长类动物模型的土拉菌病和类鼻疽。对感染进行成像的能力将提供比更传统的非人灵长类动物疾病模型更大的优势，因为它允许从每只动物收集关于感染的时间和空间模式的额外数据。此外，我们相信有可能收集有关组织中细菌代谢状态的数据。通过感染光学成像获得的额外数据将有利于提供额外信息，以支持临床前研究和将产品推进到人体I期临床安全性试验。此外，从每只动物获得额外数据的能力可以减少这些计划中使用的动物总数，例如通过提供来自单个动物的多个时间点数据。我们认为，开发可应用于非人灵长类动物的灵敏、非侵入性成像技术是未来针对选择性病原体细菌的临床干预措施的重要一步。本申请的目的是应用最新的进展，在整个动物生物发光和荧光成像研究的发病机制和治疗类鼻疽和鼻疽在绒猴。这将通过对感染动物全血的全基因组转录微阵列分析来补充，以提供对感染的免疫反应的深入了解。考虑到在密闭环境中进行的非人灵长类动物研究的高成本和后勤限制，结合这些非致死性分析方法将提供感染动态和治疗反应的全面情况，同时减少每次研究所需的动物数量。 PHS 398/2650（Rev.11/07） 第12页 续页格式