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Abstract：
Plasmodium falciparum, the deadly protozoan parasite responsible for malaria, has a tightly regulated gene expression profile closely linked to its intraerythrocytic development cycle. Epigenetic modifiers of the histone acetylation code have been identified as key regulators of the parasite\'s transcriptome but require further investigation. In this study, we map the genomic distribution of Plasmodium falciparum histone deacetylase 1 (PfHDAC1) across the erythrocytic asexual development cycle and find it has a dynamic occupancy over a wide array of developmentally relevant genes. Overexpression of PfHDAC1 results in a progressive increment in parasite load over consecutive rounds of the asexual infection cycle and is associated with enhanced gene expression of multiple families of host cell invasion factors (merozoite surface proteins, rhoptry proteins, etc.) and with increased merozoite invasion efficiency. With the use of class-specific inhibitors, we demonstrate that PfHDAC1 activity in parasites is crucial for timely intraerythrocytic development. Interestingly, overexpression of PfHDAC1 results in decreased sensitivity to frontline-drug dihydroartemisinin in parasites. Furthermore, we identify that artemisinin exposure can interfere with PfHDAC1 abundance and chromatin occupancy, resulting in enrichment over genes implicated in response/resistance to artemisinin. Finally, we identify that dihydroartemisinin exposure can interrupt the in vitro catalytic deacetylase activity and post-translational phosphorylation of PfHDAC1, aspects that are crucial for its genomic function. Collectively, our results demonstrate PfHDAC1 to be a regulator of critical functions in asexual parasite development and host invasion, which is responsive to artemisinin exposure stress and deterministic of resistance to it.
OBJECTIVE: Malaria is a major public health problem, with the parasite Plasmodium falciparum causing most of the malaria-associated mortality. It is spread by the bite of infected mosquitoes and results in symptoms such as cyclic fever, chills, and headache. However, if left untreated, it can quickly progress to a more severe and life-threatening form. The World Health Organization currently recommends the use of artemisinin combination therapy, and it has worked as a gold standard for many years. Unfortunately, certain countries in southeast Asia and Africa, burdened with a high prevalence of malaria, have reported cases of drug-resistant infections. One of the major problems in controlling malaria is the emergence of artemisinin resistance. Population genomic studies have identified mutations in the Kelch13 gene as a molecular marker for artemisinin resistance. However, several reports thereafter indicated that Kelch13 is not the main mediator but rather hinted at transcriptional deregulation as a major determinant of drug resistance. Earlier, we identified PfGCN5 as a global regulator of stress-responsive genes, which are known to play a central role in artemisinin resistance generation. In this study, we have identified PfHDAC1, a histone deacetylase as a cell cycle regulator, playing an important role in artemisinin resistance generation. Taken together, our study identified key transcriptional regulators that play an important role in artemisinin resistance generation.
OBJECTIVE: Malaria is a major public health problem, with the parasite Plasmodium falciparum causing most of the malaria-associated mortality. It is spread by the bite of infected mosquitoes and results in symptoms such as cyclic fever, chills, and headache. However, if left untreated, it can quickly progress to a more severe and life-threatening form. The World Health Organization currently recommends the use of artemisinin combination therapy, and it has worked as a gold standard for many years. Unfortunately, certain countries in southeast Asia and Africa, burdened with a high prevalence of malaria, have reported cases of drug-resistant infections. One of the major problems in controlling malaria is the emergence of artemisinin resistance. Population genomic studies have identified mutations in the Kelch13 gene as a molecular marker for artemisinin resistance. However, several reports thereafter indicated that Kelch13 is not the main mediator but rather hinted at transcriptional deregulation as a major determinant of drug resistance. Earlier, we identified PfGCN5 as a global regulator of stress-responsive genes, which are known to play a central role in artemisinin resistance generation. In this study, we have identified PfHDAC1, a histone deacetylase as a cell cycle regulator, playing an important role in artemisinin resistance generation. Taken together, our study identified key transcriptional regulators that play an important role in artemisinin resistance generation.
摘要：
恶性疟原虫,导致疟疾的致命原生动物寄生虫，具有与其红细胞内发育周期密切相关的严格调控的基因表达谱。组蛋白乙酰化密码的表观遗传修饰因子已被确定为寄生虫转录组的关键调节因子，但需要进一步研究。在这项研究中,我们绘制了恶性疟原虫组蛋白脱乙酰酶1（PfHDAC1）在整个红细胞无性发育周期中的基因组分布，并发现它对多种发育相关基因具有动态占用。PfHDAC1的过表达导致无性感染周期的连续轮次中寄生虫负荷的逐步增加，并且与多个宿主细胞侵袭因子家族的基因表达增强有关（裂殖子表面蛋白，rhoptry蛋白质，等。)并具有增加的裂殖子侵入效率。随着类特异性抑制剂的使用，我们证明寄生虫中的PfHDAC1活性对于及时的红细胞内发育至关重要.有趣的是,PfHDAC1的过表达导致寄生虫对一线药物双氢青蒿素的敏感性降低。此外，我们发现青蒿素暴露会干扰PfHDAC1丰度和染色质占用，导致与青蒿素反应/抗性有关的基因富集。最后,我们确定双氢青蒿素暴露可以中断PfHDAC1的体外催化脱乙酰酶活性和翻译后磷酸化，这对其基因组功能至关重要。总的来说，我们的结果表明，PfHDAC1是无性寄生虫发育和宿主入侵中关键功能的调节剂，对青蒿素暴露压力有反应，对青蒿素的抗性具有确定性。
目的：疟疾是一个主要的公共卫生问题，寄生虫恶性疟原虫导致大部分与疟疾相关的死亡率。它通过被感染的蚊子叮咬传播，并导致周期性发烧等症状，发冷,和头痛。然而,如果不及时治疗，它可以迅速发展到更严重和危及生命的形式。世界卫生组织目前建议使用青蒿素联合疗法,多年来一直是黄金标准。不幸的是,东南亚和非洲的某些国家，疟疾发病率很高，报告了耐药感染病例。控制疟疾的主要问题之一是青蒿素耐药性的出现。群体基因组研究已经确定Kelch13基因中的突变是青蒿素抗性的分子标记。然而,此后的几篇报道表明，Kelch13不是主要的介体，而是暗示转录失调是耐药性的主要决定因素。早些时候，我们将PfGCN5确定为应激反应基因的全局调节因子，已知在青蒿素抗性产生中起着核心作用。在这项研究中,我们已经确定了PfHDAC1，一种组蛋白脱乙酰酶作为细胞周期调节因子，在青蒿素抗性产生中发挥重要作用。一起来看,我们的研究确定了在青蒿素抗性产生中起重要作用的关键转录调节因子。
目的：疟疾是一个主要的公共卫生问题，寄生虫恶性疟原虫导致大部分与疟疾相关的死亡率。它通过被感染的蚊子叮咬传播，并导致周期性发烧等症状，发冷,和头痛。然而,如果不及时治疗，它可以迅速发展到更严重和危及生命的形式。世界卫生组织目前建议使用青蒿素联合疗法,多年来一直是黄金标准。不幸的是,东南亚和非洲的某些国家，疟疾发病率很高，报告了耐药感染病例。控制疟疾的主要问题之一是青蒿素耐药性的出现。群体基因组研究已经确定Kelch13基因中的突变是青蒿素抗性的分子标记。然而,此后的几篇报道表明，Kelch13不是主要的介体，而是暗示转录失调是耐药性的主要决定因素。早些时候，我们将PfGCN5确定为应激反应基因的全局调节因子，已知在青蒿素抗性产生中起着核心作用。在这项研究中,我们已经确定了PfHDAC1，一种组蛋白脱乙酰酶作为细胞周期调节因子，在青蒿素抗性产生中发挥重要作用。一起来看,我们的研究确定了在青蒿素抗性产生中起重要作用的关键转录调节因子。
