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

迫切需要开发更有效的疫苗和抗生素方案来对抗许多 选择对人类造成致命感染的致病细菌。对于候选人来说尤其如此 生物恐怖主义特工，伯克霍尔德里亚。马来伯克霍尔德氏菌(Burkholderia Mallei，BM)和假单胞菌(Posomallei，BP) 人类类鼻疽和腺体。这些革兰氏阴性的兼性细胞内病原体有许多共同之处 它们的遗传学、发病机制、宿主免疫反应和临床病理的共同特征。马利氏杆菌 主要感染单足动物，但可通过摄食、皮肤或气雾剂传播给人类 曝光。对这种细菌和关系非常密切的假鼻疽杆菌的关注已经加剧。 因为病原体看似完美的特征，可以恶意地用作生物恐怖或生物武器 针对动物和人类的武器。在现代，他们对公众的潜在破坏性影响 由于病原体对糖尿病的机会性感染和免疫功能受损，健康状况已升级 人，世界上两个不断增长的人口。对于这两种病原体来说，人类的严重感染具有很高的 死亡率，都是对抗生素治疗顽固的，而且没有获得许可的预防性或 治疗用途。 传染病的小动物模型在旨在识别 可被利用来设计改进的诊断、预治疗和治疗的线索和方法 打击生物恐怖主义特工。然而，有希望的线索的进一步发展取决于额外的 感染的动物模型更能真实地代表人类。显然，高质量的大型车身 目前由NIAID资助的生物防御研究将确定有希望的疾病控制新方法，以及 这些方法的发展将依赖于可靠、可重复和相关的 感染。考虑到这一点，我们提出了一项UO1项目，以开发非人类灵长类类鼻喉病模型 和腺体，可以直接对感染进行光学成像。这项工作建立在我们目前的NIAID基础上 设计非人类灵长类动物图拉拉血症和类鼻疽病模型的项目。想象感染的能力 将提供比更传统的非人类灵长类疾病模型显著的优势，因为它 允许从每种动物收集关于感染的时间和空间模式的额外数据。在……里面 此外，我们相信有可能收集有关细菌在组织中的代谢状态的数据。这个 通过感染的光学成像获得的额外数据将在提供额外信息方面有好处 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。另外， 从每只动物身上获取额外数据的能力可能会减少在 这些程序，例如，通过提供来自单个动物的多个时间点数据。 我们相信，敏感的、非侵入性成像技术的发展可以应用于 非人灵长类是未来临床干预药物选择的关键步骤 细菌。这一应用的目的是应用全动物生物发光的最新进展和 荧光成像研究绒猴类鼻疽和腺体的发病机制和治疗。这 将由全基因组转录微阵列分析感染患者的全血来补充 为动物提供对感染的免疫反应的深入观察。考虑到高昂的成本和 在围堵中进行的非人类灵长类研究的后勤限制，结合了这些非致命性 分析方法将提供感染动态和应对的全面图景 治疗，同时减少每项研究所需的动物数量。 PHS 398/2650(11/07版)第12页延续格式页

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