A new experimental model for assessing drug efficacy against Trypanosoma cruzi infection based on highly sensitive in vivo imaging.
A new experimental model for assessing drug efficacy against Trypanosoma cruzi infection based on highly sensitive in vivo imaging.
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DOI：
10.1177/1087057114552623
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发表时间：
2015-01
影响因子：
--
通讯作者：
Kelly JM
中科院分区：
文献类型：
--
作者：
Lewis MD;Francisco AF;Taylor MC;Kelly JM
原生动物克氏锥虫是恰加斯病的病原体，恰加斯病是世界上主要被忽视的传染病之一。虽然开发改进的抗寄生虫药物被认为是一个优先事项，但在过去40年里，治疗方面没有取得重大进展。进展有限的因素包括对发病机制、组织趋向性和疾病进展的不完全理解。此外，在整个慢性感染阶段追踪寄生虫负担的体内模型一直缺乏。为了解决这些问题，我们开发了一种基于生物发光T.克氏体的高灵敏度体内成像系统，克氏T.克氏体表达一种红移荧光素酶，在光谱的组织穿透橙红色区域发光。这种非侵入性小鼠模型的高度敏感性已被用于在整个慢性阶段实时监测寄生虫负担，从而确定胃肠道是长期感染的主要生态位，并证明了恰加斯心脏病可以在没有局部持久性寄生虫的情况下发展。在这里，我们回顾了成像系统的参数，并描述了如何将该实验模型纳入药物开发计划，作为评估对急性和慢性克氏T.感染疗效的有价值的工具。
The protozoan Trypanosoma cruzi is the causative agent of Chagas disease, one of the world’s major neglected infections. Although development of improved antiparasitic drugs is considered a priority, there have been no significant treatment advances in the past 40 years. Factors that have limited progress include an incomplete understanding of pathogenesis, tissue tropism, and disease progression. In addition, in vivo models, which allow parasite burdens to be tracked throughout the chronic stage of infection, have been lacking. To address these issues, we have developed a highly sensitive in vivo imaging system based on bioluminescent T. cruzi, which express a red-shifted luciferase that emits light in the tissue-penetrating orange-red region of the spectrum. The exquisite sensitivity of this noninvasive murine model has been exploited to monitor parasite burden in real time throughout the chronic stage, has allowed the identification of the gastrointestinal tract as the major niche of long-term infection, and has demonstrated that chagasic heart disease can develop in the absence of locally persistent parasites. Here, we review the parameters of the imaging system and describe how this experimental model can be incorporated into drug development programs as a valuable tool for assessing efficacy against both acute and chronic T. cruzi infections.
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