Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular <italic toggle="yes">Trypanosoma cruzi</italic> Amastigotes

ABSTRACT The mammalian stages of the parasite Trypanosoma cruzi, the causative agent of Chagas disease, exhibit a wide host species range and extensive within-host tissue distribution. These features, coupled with the ability of the parasites to persist for the lifetime of the host, suggest an inher...

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Autores principales:	Peter C. Dumoulin, Barbara A. Burleigh
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Chagas amastigote benznidazole cell cycle plasticity stress Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4a602db582fa4b54a4330a915625901f
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spelling	oai:doaj.org-article:4a602db582fa4b54a4330a915625901f2021-11-15T16:00:15ZStress-Induced Proliferation and Cell Cycle Plasticity of Intracellular <italic toggle="yes">Trypanosoma cruzi</italic> Amastigotes10.1128/mBio.00673-182150-7511https://doaj.org/article/4a602db582fa4b54a4330a915625901f2018-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00673-18https://doaj.org/toc/2150-7511ABSTRACT The mammalian stages of the parasite Trypanosoma cruzi, the causative agent of Chagas disease, exhibit a wide host species range and extensive within-host tissue distribution. These features, coupled with the ability of the parasites to persist for the lifetime of the host, suggest an inherent capacity to tolerate changing environments. To examine this potential, we studied proliferation and cell cycle dynamics of intracellular T. cruzi amastigotes experiencing transient metabolic perturbation or drug pressure in the context of an infected mammalian host cell. Parasite growth plasticity was evident and characterized by rapid and reversible suppression of amastigote proliferation in response to exogenous nutrient restriction or exposure to metabolic inhibitors that target glucose metabolism or mitochondrial respiration. In most instances, reduced parasite proliferation was accompanied by the accumulation of amastigote populations in the G1 phase of the cell cycle, in a manner that was rapidly and fully reversible upon release from the metabolic block. Acute amastigote cell cycle changes at the G1 stage were similarly observed following exposure to sublethal concentrations of the first-line therapy drug, benznidazole, and yet, unlike the results seen with inhibitors of metabolism, recovery from exposure occurred at rates inversely proportional to the concentration of benznidazole. Our results show that T. cruzi amastigote growth plasticity is an important aspect of parasite adaptation to stress, including drug pressure, and is an important consideration for growth-based drug screening. IMPORTANCE Infection with the intracellular parasite Trypanosoma cruzi can cause debilitating and potentially life-threatening Chagas disease, where long-term parasite persistence is a critical determinant of clinical disease progression. Such tissue-resident T. cruzi amastigotes are refractory to immune-mediated clearance and to drug treatment, suggesting that in addition to exploiting immune avoidance mechanisms, amastigotes can facilitate their survival by adapting flexibly to diverse environmental stressors. We discovered that T. cruzi intracellular amastigotes exhibit growth plasticity as a strategy to adapt to and rebound from environmental stressors, including metabolic blockades, nutrient starvation, and sublethal exposure to the first-line therapy drug benznidazole. These findings have important implications for understanding parasite persistence, informing drug development, and interpreting drug efficacy.Peter C. DumoulinBarbara A. BurleighAmerican Society for MicrobiologyarticleChagasamastigotebenznidazolecell cycleplasticitystressMicrobiologyQR1-502ENmBio, Vol 9, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Chagas amastigote benznidazole cell cycle plasticity stress Microbiology QR1-502
spellingShingle	Chagas amastigote benznidazole cell cycle plasticity stress Microbiology QR1-502 Peter C. Dumoulin Barbara A. Burleigh Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular <italic toggle="yes">Trypanosoma cruzi</italic> Amastigotes
description	ABSTRACT The mammalian stages of the parasite Trypanosoma cruzi, the causative agent of Chagas disease, exhibit a wide host species range and extensive within-host tissue distribution. These features, coupled with the ability of the parasites to persist for the lifetime of the host, suggest an inherent capacity to tolerate changing environments. To examine this potential, we studied proliferation and cell cycle dynamics of intracellular T. cruzi amastigotes experiencing transient metabolic perturbation or drug pressure in the context of an infected mammalian host cell. Parasite growth plasticity was evident and characterized by rapid and reversible suppression of amastigote proliferation in response to exogenous nutrient restriction or exposure to metabolic inhibitors that target glucose metabolism or mitochondrial respiration. In most instances, reduced parasite proliferation was accompanied by the accumulation of amastigote populations in the G1 phase of the cell cycle, in a manner that was rapidly and fully reversible upon release from the metabolic block. Acute amastigote cell cycle changes at the G1 stage were similarly observed following exposure to sublethal concentrations of the first-line therapy drug, benznidazole, and yet, unlike the results seen with inhibitors of metabolism, recovery from exposure occurred at rates inversely proportional to the concentration of benznidazole. Our results show that T. cruzi amastigote growth plasticity is an important aspect of parasite adaptation to stress, including drug pressure, and is an important consideration for growth-based drug screening. IMPORTANCE Infection with the intracellular parasite Trypanosoma cruzi can cause debilitating and potentially life-threatening Chagas disease, where long-term parasite persistence is a critical determinant of clinical disease progression. Such tissue-resident T. cruzi amastigotes are refractory to immune-mediated clearance and to drug treatment, suggesting that in addition to exploiting immune avoidance mechanisms, amastigotes can facilitate their survival by adapting flexibly to diverse environmental stressors. We discovered that T. cruzi intracellular amastigotes exhibit growth plasticity as a strategy to adapt to and rebound from environmental stressors, including metabolic blockades, nutrient starvation, and sublethal exposure to the first-line therapy drug benznidazole. These findings have important implications for understanding parasite persistence, informing drug development, and interpreting drug efficacy.
format	article
author	Peter C. Dumoulin Barbara A. Burleigh
author_facet	Peter C. Dumoulin Barbara A. Burleigh
author_sort	Peter C. Dumoulin
title	Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular <italic toggle="yes">Trypanosoma cruzi</italic> Amastigotes
title_short	Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular <italic toggle="yes">Trypanosoma cruzi</italic> Amastigotes
title_full	Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular <italic toggle="yes">Trypanosoma cruzi</italic> Amastigotes
title_fullStr	Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular <italic toggle="yes">Trypanosoma cruzi</italic> Amastigotes
title_full_unstemmed	Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular <italic toggle="yes">Trypanosoma cruzi</italic> Amastigotes
title_sort	stress-induced proliferation and cell cycle plasticity of intracellular <italic toggle="yes">trypanosoma cruzi</italic> amastigotes
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/4a602db582fa4b54a4330a915625901f
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Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular <italic toggle="yes">Trypanosoma cruzi</italic> Amastigotes

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