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

• Published in: Science translational medicine Vol. 12; no. 567
• Main Authors: Bustamante, Juan M, Sanchez-Valdez, Fernando, Padilla, Angel M, White, Brooke, Wang, Wei, Tarleton, Rick L
• Format: Journal Article
• Language: English
• Published: United States 28.10.2020
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.abb7656

A major contributor to treatment failure in Chagas disease, caused by infection with the protozoan parasite , is that current treatment regimens do not address the drug insensitivity of transiently dormant 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 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 may not be fully resistant to trypanocidal compounds such as benznidazole. Collectively, these studies provide important information on the phenomenon of dormancy in 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.