Spontaneous dormancy protects Trypanosoma cruzi during extended drug exposure

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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.

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Fernando J Sánchez-Valdéz

Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, United States

Competing interests
The authors declare that no competing interests exist.
Angel Padilla

Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, United States

Competing interests
The authors declare that no competing interests exist.
Wei Wang

Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, United States

Competing interests
The authors declare that no competing interests exist.
Dylan Orr

Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, United States

Competing interests
The authors declare that no competing interests exist.
Rick L Tarleton

Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, United States

For correspondence
tarleton@uga.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9589-5243

Funding

National Institutes of Health (AI108265)

Rick L Tarleton

National Institutes of Health (AI124692)

Rick L Tarleton

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol A2015 05-010-R3 approved by the University of Georgia Institutional Animal Care and Use Committee under Animal Welfare Assurance #A3437-01.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.