Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular Trypanosoma cruzi Amastigotes
Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular Trypanosoma cruzi Amastigotes
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DOI：
10.1128/mbio.00673-18
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发表时间：
2018-07-01
期刊：
影响因子：
6.4
通讯作者：
Burleigh, Barbara A.
中科院分区：
文献类型：
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作者：
Dumoulin, Peter C.;Burleigh, Barbara A.
寄生虫克氏锥虫（锥虫病的病原体）的哺乳动物阶段表现出广泛的宿主物种范围和广泛的宿主组织内分布。这些特征，再加上寄生虫在宿主一生中持续存在的能力，表明它们具有耐受不断变化的环境的内在能力。为了检验这种潜力，我们研究了细胞内T细胞的增殖和细胞周期动力学。在受感染的哺乳动物宿主细胞中经历瞬时代谢扰动或药物压力的克氏无鞭毛体。寄生虫的生长可塑性是明显的，其特征是响应于外源性营养限制或暴露于靶向葡萄糖代谢或线粒体呼吸的代谢抑制剂，快速和可逆地抑制无鞭毛体增殖。在大多数情况下，寄生虫增殖的减少伴随着细胞周期G（1）期无鞭毛体种群的积累，其方式是在从代谢阻断中释放后迅速和完全可逆的。在暴露于亚致死浓度的一线治疗药物苄硝唑后，也观察到G（1）期的急性无鞭毛体细胞周期变化，然而，与代谢抑制剂的结果不同，暴露后的恢复率与苄硝唑的浓度成反比。结果表明，T. cruzi无鞭毛体的生长可塑性是寄生虫适应压力，包括药物压力的一个重要方面，是一个重要的考虑因素，为增长为基础的药物screening.Importance感染细胞内寄生虫锥虫cruzi可以导致衰弱和潜在的危及生命的恰加斯病，其中长期寄生虫的持续性是临床疾病进展的一个关键决定因素。这种组织驻留T. Cruzi无鞭毛体对免疫介导的清除和药物治疗是难治的，这表明除了利用免疫回避机制之外，无鞭毛体还可以通过灵活地适应不同的环境应激源来促进它们的存活。我们发现T. Cruzi细胞内无鞭毛体表现出生长可塑性，作为适应环境应激源和从环境应激源反弹的策略，所述环境应激源包括代谢阻断、营养饥饿和亚致死暴露于一线治疗药物苯并咪唑。这些发现对于了解寄生虫的持久性，为药物开发提供信息和解释药物疗效具有重要意义。
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 G(1) 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 G(1) 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 Trypanosorna 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.