Linking metabolite sensing and gene expression in malaria parasites

将疟疾寄生虫的代谢物传感和基因表达联系起来

• 批准号: 10593642
• 负责人: Manoj T Duraisingh
• 金额: $ 19.94万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-09 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593642
• 关键词: Anopheles Genus; Bacterial Infections; Biology; Blood; Blood Circulation; Cell Hypoxia; Cell physiology; Cells; Code; Complex; Culicidae; Daughter; Development; Disease; Environment; Epigenetic Process; Erythrocytes; Etiology; Family; Gene Expression; Genes; Genetic Transcription; Glycolysis; Growth; Histone Code; Histones; Human; Human Bites; Immune; In Vitro; India; Infection; Investigation; Laboratories; Lactic Acidosis; Life; Link; Lysine; Macrophage; Malaria; Mammalian Cell; Maps; Mediating; Mediator; Metabolic; Metabolism; Mus; Parasites; Pathogenesis; Pathway interactions; Patient Isolation; Phenotype; Physiological; Plasmodium; Plasmodium falciparum; Post-Translational Protein Processing; Production; Proliferating; Proteins; Pyruvate; Reporting; Role; Severity of illness; Sirtuins; Symptoms; Tail; Virulence; Work; aerobic glycolysis; anaerobic glycolysis; asexual; malaria infection; novel; programs; response; transcriptome sequencing; transmission process; virulence gene

Malaria is a life-threatening disease that is transmitted to humans by the bite of Anopheline mosquitoes infected with Plasmodium parasites. Proliferation of parasites within erythrocytes in the bloodstream is central to the parasite’s survival and results in the pathogenesis of malaria. Little is known about how the metabolic environment of the parasite is sensed and linked to changes in gene expression. One of the major factors underlying severe malaria, caused by infection with Plasmodium falciparum, is lactic acidosis, which has a complex etiology, with lactate being produced by both the parasite and the host. During the asexual stages, P. falciparum parasites carry out fermentative glycolysis leading to the conversion of pyruvate into lactate. In addition, the host, due to aerobic glycolysis in proliferating immune cells and anaerobic glycolysis in hypoxic cells, contributes to increased lactate levels in the bloodstream. In vitro studies have shown that the parasite responds to changes in host lactate levels. Lactate accumulation can retard parasite growth, alter the rate of switching to transmissible forms, and has been associated with virulence gene expression. However, the mechanism underlying these profound changes in parasite phenotypes is unknown. In a recent study, a new post-translational modification (PTM), lactylation, was reported in human and mouse cells, that responds to lactate levels. In mammalian cells, several hundred proteins including histones are lactylated, and increased lactate levels in the course of a bacterial infection resulted in gene expression changes in macrophages, providing a link between cellular metabolism and gene expression. We have discovered this new PTM on the tails of multiple histones in P. falciparum. We hypothesize that lactate-derived lactylation of parasite histones is a novel histone code signature that mediates gene expression changes linked to lactate metabolism. We will comprehensively assess histone lactylation dynamics through the parasite asexual cycle as well as the ability of histone lactylation to be altered by perturbations in lactate metabolism. These investigations will be performed both in a diverse panel of laboratory strains, as well as patient isolates with different disease severity. We will also identify the target genes of histone lactylation and their association with transcriptional programs linked to parasite cellular processes. The findings from this proposed work have the potential to establish a critical role for histone lactylation at the fulcrum between lactate metabolism and gene expression in asexual stages of P. falciparum, with significant implications for malaria pathogenesis and transmission.

疟疾是一种威胁生命的疾病，通过受感染的按蚊叮咬传播给人类 疟原虫寄生虫寄生虫在血流中红细胞内的增殖是血液循环的核心。 寄生虫的生存和疟疾的发病机制的结果。人们对新陈代谢是如何 寄生虫的环境被感知并与基因表达的变化相关联。的主要因素之一 由恶性疟原虫感染引起的潜在严重疟疾是乳酸酸中毒， 复杂的病因学，由寄生虫和宿主产生乳酸。在无性繁殖阶段，P. 恶性疟原虫进行发酵糖酵解，导致丙酮酸转化为乳酸。在 此外，宿主由于增殖免疫细胞中的有氧糖酵解和缺氧环境中的无氧糖酵解， 细胞，有助于增加血液中的乳酸水平。体外研究表明， 对宿主乳酸水平的变化做出反应。乳酸积累可以延缓寄生虫的生长，改变寄生虫的生长速率， 转化为可传播的形式，并与毒力基因表达有关。但 寄生虫表型发生这些深刻变化的机制尚不清楚。在最近的一项研究中， 翻译后修饰（PTM），乳酰化，在人类和小鼠细胞中报道， 乳酸水平。在哺乳动物细胞中，包括组蛋白在内的数百种蛋白质被乳酸化， 细菌感染过程中的乳酸水平导致巨噬细胞中的基因表达变化， 提供细胞代谢和基因表达之间的联系。我们已经发现了这个新的PTM上的 恶性疟原虫中多组蛋白的尾部。我们假设寄生虫组蛋白的乳酸衍生的乳酸化是 一种新的组蛋白编码签名，介导与乳酸代谢相关的基因表达变化。我们将 通过寄生虫无性周期全面评估组蛋白乳酸化动力学以及 组蛋白乳酸化被乳酸代谢的扰动改变。这些调查将在 在不同的实验室菌株组以及具有不同疾病严重程度的患者分离株中。我们将 还确定了组蛋白乳酸化的靶基因及其与转录程序的关联， 寄生的细胞过程。这项拟议工作的结果有可能确立一个关键作用， 组蛋白乳酸化是乳酸代谢和基因表达的支点。 恶性疟原虫，对疟疾发病机制和传播具有重要意义。