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: 8264810
• 负责人: FREDERICK D QUINN
• 金额: $ 100.62万
• 依托单位: UNIVERSITY OF GEORGIA
• 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 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264810
• 关键词: Non; invasive; Optical; Imaging; Select

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

迫切需要针对许多许多人开发更有效的疫苗和抗生素方案 选择引起人类致命感染的剂细菌。候选人尤其如此 Burkholderia生物恐怖主义者。假单胞菌（BP）和Burkholderia Mallei（BM）， 人类黑胶病和腺体。这些革兰氏阴性，辅助细胞内病原体共享许多 其遗传学，发病机理，宿主免疫反应和临床病理的常见特征。 B. Mallei 主要感染溶剂，但该疾病是通过摄入和皮肤或气溶胶传播的。 暴露。对该细菌和密切相关的物种的关注B.伪小膜增强了 由于病原体看似完美的特征，可用于生物越或生物处理 针对动物和人类的武器。在现代，它们对公众的潜在破坏性影响 由于病原体对糖尿病和免疫功能低下的机会感染，健康状况升级了 人们，全世界有两个不断增长的人口。对于两种病原体，人类的严重感染都具有很高的 死亡率均是抗生素疗法的顽固性，并且不存在预防性或 治疗用途。 传染病的小动物模型在旨在识别的研究计划中起着核心作用 可以利用可以利用改进诊断，预处理和疗法的铅和方法 反对生物恐怖主义者。但是，有希望的潜在客户的进一步发展取决于其他 感染动物模型，更忠实地代表人类。很明显，高质量的巨大机构 当前由NIAID资助的Biodefense研究将确定有希望的新方法来控制疾病， 这些方法的开发将取决于可靠的，可重复的和相关的模型 感染。考虑到这一点，我们提出了一个UO1项目，以开发非人类灵长类动物模型 和允许感染直接光学成像的腺体。这项工作是基于我们当前的Niaid 旨在设计tular症和黑胶病的非人类灵长类动物模型的项目。图像感染的能力 将比更常规的非人类灵长类动物模型提供重要的优势，因为它 允许从每只动物收集感染的时间和空间模式的其他数据。在 此外，我们认为可以收集有关组织中细菌代谢状态的数据。这 通过光学成像获得感染获得的其他数据将有利于提供其他信息 支持临床前研究并将产品发展为I期临床安全试验。还， 从每只动物中获取其他数据的能力可以减少使用的动物的总数 这些程序，例如通过提供单个动物的多个时间点数据。 我们认为，可以应用于敏感的非侵入性成像技术的发展 非人类灵长类动物是生成未来临床干预措施的重要步骤 细菌。本应用的目的是应用全动物生物发光的最新进展和 荧光成像研究果果中黑酚和腺体的发病机理和治疗。这 全基因组的转录微阵列分析被感染的全血。 动物可以深入了解感染的免疫学反应。鉴于高昂的成本和 在遏制中进行的非人类灵长类动物研究的后勤约束，结合了这些非致命 分析方法将提供有关感染动态和反应的全面图景 治疗，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

项目成果

In vivo bioluminescence imaging of Escherichia coli O104:H4 and role of aerobactin during colonization of a mouse model of infection.

• DOI: 10.1186/1471-2180-12-112
• 发表时间: 2012-06-20
• 期刊: BMC microbiology
• 影响因子: 4.2
• 作者: Torres AG;Cieza RJ;Rojas-Lopez M;Blumentritt CA;Souza CS;Johnston RK;Strockbine N;Kaper JB;Sbrana E;Popov VL
• 通讯作者: Popov VL

Use of the common marmoset to study Burkholderia mallei infection.

• DOI: 10.1371/journal.pone.0124181
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Jelesijevic T;Zimmerman SM;Harvey SB;Mead DG;Shaffer TL;Estes DM;Michel F;Quinn FD;Hogan RJ;Lafontaine ER
• 通讯作者: Lafontaine ER