Linking metabolite sensing and gene expression in malaria parasites

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。 带着疟原虫寄生虫。血液中红细胞内寄生虫的增殖是 寄生虫的存活和导致疟疾的发病。对新陈代谢是如何产生的知之甚少 寄生虫的环境被感知并与基因表达的变化联系在一起。其中一个主要因素是 由感染恶性疟原虫引起的严重疟疾是乳酸中毒，它有一种 病原学复杂，乳酸由寄生虫和宿主共同产生。在无性生殖阶段，P. 恶性寄生虫进行发酵糖酵解，将丙酮酸转化为乳酸。在……里面 此外，宿主由于增殖免疫细胞中的有氧糖酵解和低氧中的厌氧糖酵解 细胞，有助于增加血液中的乳酸水平。体外研究表明，这种寄生虫 对宿主乳酸水平的变化做出反应。乳酸蓄积可以延缓寄生虫的生长，改变 转变为可传播的形式，并与毒力基因表达有关。然而， 寄生虫表型的这些深刻变化背后的机制尚不清楚。在最近的一项研究中，一项新的 翻译后修饰(PTM)，乳糖化，在人类和小鼠细胞中被报道，它对 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糖化，并增加 细菌感染过程中的乳酸水平导致巨噬细胞基因表达的变化， 提供细胞新陈代谢和基因表达之间的联系。我们已经发现了这种新的PTM 恶性疟原虫多个组蛋白的尾部。我们假设寄生虫组蛋白的乳酸衍生乳糖化是 一种新奇的组蛋白密码签名，它介导与乳酸代谢相关的基因表达变化。我们会 通过寄生虫的无性循环综合评估组蛋白乳糖化的动态以及 组蛋白乳糖化受乳酸代谢的干扰而改变。这些调查将被执行 在一组不同的实验室菌株中，以及不同疾病严重程度的患者分离株中。我们会 还要确定组蛋白乳糖化的目标基因及其与转录程序的关联 寄生虫的细胞过程。这项拟议工作的发现有可能确立一个关键角色 组蛋白乳糖化在无性阶段乳酸代谢和基因表达之间的支点。 恶性疟原虫，对疟疾的发病和传播具有重要意义。

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.