Spontaneous dormancy protects Trypanosoma cruzi during extended drug exposure

Sánchez-Valdéz, Fernando; Padilla, Ángel M.; Wang, Wei; Orr, Dylan; Tarleton, Rick L.

doi:10.7554/elife.34039

Cited by 186 publications

(212 citation statements)

References 30 publications

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“…While some of the amastigote parasites continue to multiply, a few of them stop their proliferation, even without drug treatment. These none-proliferating amastigotes retain their capacity to differentiate into trypomastigotes as well as their capacity to resume multiplication [34]. Interestingly, in our study, we highlight that at the trypomastigote stage, most of the strains belonging to TcI, are less susceptible (the non wild-type) to both NFX and BZN.…”

Section: Discussionmentioning

confidence: 50%

In Vitro Benznidazole and Nifurtimox Susceptibility Profile of Trypanosoma cruzi Strains Belonging to Discrete Typing Units TcI, TcII, and TcV

et al. 2019

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We ascertain the in vitro Benznidazole (BZN) and Nifurtimox (NFX) susceptibility pattern of epimastigotes, trypomastigotes, and amastigotes of 21 T. cruzi strains, from patients, reservoir, and triatomine bugs of various geographic origins. Using this panel of isolates, we compute the Epidemiological cut off value (COwt). Then, the frequency of the susceptible phenotype (Wild type) towards benznidazole (BZN) and nifurtimox (NFX) within this set of strains belonging to three discrete typing units (DTUs), TcI, TcII, and TcV, was deduced. We observed that the susceptibility status of individual T. cruzi isolates toward BZN and NFX is related to the genetic background and underlying factors that are probably related to the individual life trait history of each strain. Analyzing drug susceptibility in this conceptual framework would offer the possibility to evidence a link between isolates expressing a low susceptibility level (not wild-type) as defined by the COwt value and none-curative treatment. It will also permit us to track drug-resistant parasites in the T. cruzi population.

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Section: Discussionmentioning

confidence: 50%

In Vitro Benznidazole and Nifurtimox Susceptibility Profile of Trypanosoma cruzi Strains Belonging to Discrete Typing Units TcI, TcII, and TcV

et al. 2019

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“…This may also explain the differing response rate to anti-parasitic treatment among children in comparison with adults, as children have a T-cell profile associated with a more robust clinical response [138]. Additionally, animal model research demonstrates that a small proportion of trypomastigotes are dormant at any given time during infection, and are likely to be protected from anti-parasitic compounds in this state [139].…”

Section: Why Are There Poor Cure Rates In Chronic Patients?mentioning

confidence: 99%

WHF IASC Roadmap on Chagas Disease

et al. 2020

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Background: Chagas Disease is a neglected tropical disease caused by the protozoan Trypanosoma cruzi, with some of the most serious manifestations affecting the cardiovascular system. It is a chronic, stigmatizing condition, closely associated with poverty and affecting close to 6 million people globally. Although historically the disease was limited to endemic areas of Latin America recent years have seen an increasing global spread. In addition to the morbidity and mortality associated with the disease, the social and economic burdens on individuals and society are substantial. Often called the 'silent killer', Chagas disease is characterized by a long, asymptomatic phase in affected indivi duals. A pproximately 30% then go on develop chronic Chagas cardiomyopathy and other serious cardiac complications such as stroke, rhythm disturbances and severe heart failure. Methods: In a collaboration of the World Hearth Federation (WHF) and the Inter-American S ociety of Cardiology (IASC) a writing group consisting of 20 diverse experts on Chagas disease (CD) was convened. The group provided up to date expert knowledge based on their area of expertise. An extensive review of the literature describing obstacles to diagnosis and treatment Echeverría et al: WHF IASC Roadmap on Chagas Disease Art. 26, page 2 of 31 of CD along with proposed solutions was conducted. A survey was sent to all WHF Members and, using snowball sampling to widen the consultation, to a variety of health care professionals working in the CD global health community. The results were analyzed, open comments were reviewed and consolidated, and the findings were incorporated into this document, thus ensuring a consensus representation. Results: The WHF IASC Roadmap on Chagas Disease offers a comprehensive summary of current knowledge on prevention, diagnosis and management of the disease. In providing an analysis of 'roadblocks' in access to comprehensive care for Chagas disease patients, the document serves as a framework from which strategies for implementation such as national plans can be formulated. Several dimensions are considered in the analysis: healthcare system capabilities, governance, financing, community awareness and advocacy. Conclusion: The WHF IASC Roadmap proposes strategies and evidence-based solutions for healthcare professionals, health authorities and governments to help overcome the barriers to comprehensive care for Chagas disease patients. This roadmap describes an ideal patient care pathway, and explores the roadblocks along the way, offering potential solutions based on available research and examples in practice. It represents a call to action to decision-makers and health care professionals to step up efforts to eradicate Chagas disease.

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“…An alternative explanation for parasite persistence in the presence of azoles is a complete cessation of amastigote division. While the nature of dormancy in T. cruzi remains under investigation (Sánchez-Valdéz et al, 2018), we report here a protective mechanism that allows for amastigote proliferation in the presence of drug at the population level. Since, slowed growth appears to induce tolerance to azoles but is insufficient to provide resistance; we investigated potential mechanisms to explain the protection from azoles mediated specifically by glutamine restriction.…”

Section: Discussionmentioning

confidence: 78%

“…While spontaneous emergence of latent forms of T. cruzi offers one possible explanation for the failure to achieve parasitological cure following drug treatment (Sánchez-Valdéz et al, 2018), the role of cellular metabolic heterogeneity in recalcitrant T. cruzi infection has not been explored. In previous work, we showed that proliferation of T. cruzi intracellular amastigotes is responsive to modifications in the exogenous growth medium and that media compositions have significant and specific interactions with small molecule inhibitors of parasite metabolism, such as the cytochrome b inhibitor GNF7686 (Dumoulin and Burleigh, 2018).…”

Section: Resultsmentioning

confidence: 99%