Trypanosoma cruzi persisters that survive benznidazole treatment in vitro and in vivo are in a transient non-replicative state
Abstract
Abstract Benznidazole is the front-line drug used to treat infections with Trypanosoma cruzi , the causative agent of Chagas disease. However, for reasons that are unknown, treatment failures are common. To assess the nature of parasites that persist after treatment, we first exposed infected mammalian cell monolayers to a benznidazole regimen that reduces the intracellular amastigote population to <1% of the pre-treatment level. Of host cells that remained infected, the vast majority contained only one or two surviving intracellular amastigotes. Analysis, using incorporation of the thymidine analogue EdU, revealed these surviving parasites to be in a transient non-replicative state. Furthermore, treatment with benznidazole led to widespread damage to parasite DNA. When parasites that survived treatment in mice were examined using in vivo and ex vivo bioluminescence imaging, we found that recrudescence is not due to persistence of parasites in a specific organ or tissue that preferentially protects them from drug activity. Surviving parasites were widely distributed and located in host cells where the vast majority contained only one or two amastigotes. Therefore, infection relapse does not arise from a small number of intact large nests. Rather, persisters are either survivors of intracellular populations where co-located parasites have been killed, or amastigotes in single/low-level infected cells exist in a state where they are less susceptible to benznidazole. Assessment…
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Evidence Hub reads this as a preprint, done in animal and cell cultures (in vitro), not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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