Abstract
The ability of the Chagas disease agent Trypanosoma cruzi to resist extended in vivo exposure to highly effective trypanocidal compounds prompted us to explore the potential for dormancy and its contribution to failed drug treatments in this infection. We document the development of non-proliferating intracellular amastigotes in vivo and in vitro in the absence of drug treatment. Non-proliferative amastigotes ultimately converted to trypomastigotes and established infections in new host cells. Most significantly, dormant amastigotes were uniquely resistant to extended drug treatment in vivo and in vitro and could re-establish a flourishing infection after as many as 30 days of drug exposure. These results demonstrate a dormancy state in T. cruzi that accounts for the failure of highly cytotoxic compounds to completely resolve the infection. The ability of T. cruzi to establish dormancy throws into question current methods for identifying curative drugs but also suggests alternative therapeutic approaches.
Highlights
Parasitic diseases have been resistant to the development of effective vaccines and safe and curative therapeutic drugs
We document the occurrence of dormancy in the protozoan T. cruzi and link this phenomenon to the resistance of this parasite to otherwise highly effective and cytotoxic drugs. We show that both in vitro and in vivo, T. cruzi exhibits a biphasic kill curve, with the rapid death of most parasites but the persistence of transiently non-replicating intracellular parasites that are resistant to high level and prolonged drug exposure
To directly assess the activity of BNZ in vivo, we first established a localized infection of T. cruzi in the footpads of mice and used a transgenic luciferase reporter to monitor the loss of parasites subsequent to a single oral dose of BNZ
Summary
Parasitic diseases have been resistant to the development of effective vaccines and safe and curative therapeutic drugs. In addition to classical genetic-based drug resistance, it has become increasingly appreciated that in bacterial infections, ‘persister’ cells develop that are transiently unaffected by chemotherapy, due in most cases to metabolic dormancy (reviewed in [Harms et al, 2016]) Such persisters can arise spontaneously in the presence or absence of stress signals and can reemerge after the termination of environmental challenges – such as antibiotic treatment. We document the occurrence of dormancy in the protozoan T. cruzi and link this phenomenon to the resistance of this parasite to otherwise highly effective and cytotoxic drugs We show that both in vitro and in vivo, T. cruzi exhibits a biphasic kill curve, with the rapid death of most parasites but the persistence of transiently non-replicating intracellular parasites that are resistant to high level and prolonged drug exposure
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call