A modified drug regimen clears active and dormant trypanosomes in mouse models of Chagas disease.
A modified drug regimen clears active and dormant trypanosomes in mouse models of Chagas disease.
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DOI：
10.1126/scitranslmed.abb7656
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发表时间：
2020-10-28
影响因子：
17.1
通讯作者：
Tarleton RL
中科院分区：
文献类型：
--
作者：
Bustamante JM;Sanchez-Valdez F;Padilla AM;White B;Wang W;Tarleton RL
由原生动物寄生虫克氏锥虫感染引起的查加斯病治疗失败的一个主要原因是，目前的治疗方案没有解决暂时休眠的T.克鲁兹无鞭毛体。在这里，我们证明了在一个改进的治疗方案中使用一种目前可用的药物，即在延长的治疗期内降低频率给予更高的个体剂量，可以持续地消灭T。克氏锥虫病的三种小鼠模型中的克氏感染。每周一次以标准日剂量的2.5-5倍剂量给予苄硝唑，迅速消除了活跃复制的寄生虫，并最终根除了小鼠体内残留的短暂休眠寄生虫种群。这一结果最初在“难以治愈”的小鼠感染模型中使用免疫学、寄生虫学和分子生物学方法得到证实，并最终通过使用光片荧光显微镜（LSFM）对光学澄清组织进行的全器官分析得到证实。该工具可有效监测完整器官中的病原体负荷，包括检测单个休眠寄生虫，并评估治疗结果。基于LSFM的分析还表明，T. Cruzi可能不完全耐受杀锥虫化合物如苯并咪唑。这些研究为T. Cruzi感染的小鼠，证明了使用目前可用的药物治疗性地克服休眠的方法，并提供了监测这种以及可能的其他低密度感染因子的替代治疗方法的方法。一种改良的苄硝唑方案可预防几种查加斯病小鼠模型中的克氏锥虫休眠依赖性治疗失败。
A major contributor to treatment failure in Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi, is that current treatment regimens do not address the drug-insensitivity of transiently dormant T. cruzi amastigotes. Here, we demonstrated that use of a currently available drug in a modified treatment regimen of higher individual doses given less frequently over an extended treatment period, could consistently extinguish T. cruzi infection in three mouse models of Chagas disease. Once per week administration of benznidazole at a dose 2.5-5 times the standard daily dose rapidly eliminated actively replicating parasites and ultimately eradicated the residual, transiently dormant parasite population in mice. This outcome was initially confirmed in ‘difficult to cure’ mouse infection models using immunological, parasitological, and molecular biological approaches and ultimately corroborated by whole organ analysis of optically clarified tissues using light-sheet fluorescence microscopy (LSFM). This tool was effective for monitoring pathogen load in intact organs, including detection of individual dormant parasites, and for assessing treatment outcomes. LSFM-based analysis also suggested that dormant amastigotes of T. cruzi may not be fully resistant to trypanocidal compounds such as benznidazole. Collectively these studies provide important information on the phenomenon of dormancy in T. cruzi infection in mice, demonstrate methods to therapeutically override dormancy using a currently available drug, and provide methods to monitor alternative therapeutic approaches for this, and possibly other, low density infectious agents. A modified regimen of benznidazole prevents Trypanosoma cruzi dormancy-dependent treatment failure in several mouse models of Chagas disease.
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影响因子：
6.4
作者：
Bustamante, Juan M.;Craft, Julie M.;Tarleton, Rick L.
通讯作者：
Tarleton, Rick L.
影响因子：
4.9
作者：
Gabriela Alvarez, Maria;Hernandez, Yolanda;Viottia, Rodolfo
通讯作者：
Viottia, Rodolfo
影响因子：
5.2
作者：
Martins, H. R.;Figueiredo, L. M.;Lana, M.
通讯作者：
Lana, M.
影响因子：
4.9
作者：
Francisco, Amanda Fortes;Lewis, Michael D.;Kelly, John M.
通讯作者：
Kelly, John M.
DOI：
10.1590/s0074-02762002000100001
发表时间：
2002-01-01
期刊：
Memórias do Instituto Oswaldo Cruz
影响因子：
--
作者：
Coura, José Rodrigues;Castro, Solange L de
通讯作者：
Castro, Solange L de