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A modified drug regimen clears active and dormant trypanosomes in mouse models of Chagas disease

A modified regimen of benznidazole prevents Trypanosoma cruzi dormancy-dependent treatment failure in several mouse models of Chagas disease. Trouncing trypanosomes Trypanosoma cruzi infection causes Chagas disease in millions of individuals in Latin America, and intensive drug treatment is frequently unsuccessful. Bustamante et al. demonstrated that high weekly doses of oral benznidazole over 30 weeks, rather than the current treatment of smaller twice-daily doses over 2 months, resulted in better clearance of both actively replicating and dormant trypanosomes in mouse models of Chagas disease. The clearance of dormant parasites was confirmed by light sheet fluorescence microscopy, which allowed the authors to image whole organs and intact tissues of infected mice. Further studies will determine if this drug regimen will be successful for treating those with Chagas disease. 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 to 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.