Gluconeogenesis: Adding a new piece to the puzzle of malaria parasitism

    碳水化合物代谢紊乱，包括低血糖和乳酸酸中毒，是疟疾的常见特征。低血糖是恶性疟原虫感染造成死亡的独立危险因素，其产生机制被认为是由疾病引起的厌食症、肝葡萄糖生成（hepatic glucose production）失调和疟原虫及免疫细胞对葡萄糖的消耗。而恶性疟原虫的增殖依赖于葡萄糖，降低浓度可以诱导其固缩，热量限制引起的血糖降低和糖酵解抑制对疟原虫（Pcc AS）感染的小鼠具有保护作用。

    2022年7月15日，Miguel P. Soares团队在《细胞代谢》期刊发表了题为“A hypometabolic defense strategy against malaria”的文章，发现宿主葡萄糖-6-磷酸酶催化亚基 1 (G6Pc1) 对糖异生和血糖的调节是影响疟原虫复制和疾病临床结局的关键代谢步骤。

   Disorders of carbohydrate metabolism, including hypoglycemia and lactic acidosis, are common features of malaria. In this issue of Cell Metabolism, Ramos et al. report that regulation of gluconeogenesis and glycemia by the host glucose-6-phosphatase catalytic subunit 1 (G6Pc1) is a key metabolic step that affects both Plasmodium replication and clinical outcome of disease.  

    他们证明与疟疾相关的低血糖症是由一种非经典的抵抗机制产生的，这种低代谢（hypometabolic ）反应可以短暂抑制肝脏葡萄糖生成可防止无约束的免疫介导炎症、器官损伤和贫血；但持续一段时间后可导致低血糖，损害宿主能量消耗和适应性体温调节。后者通过一种与寄生虫线粒体功能障碍相关的机制阻止疟原虫无性阶段的发展，疟原虫也会激活一个与降低毒性和性别分化相关的转录程序以产生可传播的配子母细胞。综上，疟疾相关低血糖代表了一种基于低代谢的防御策略，平衡了寄生虫的毒性和传播。 

A hypometabolic defense strategy against malaria

对抗疟疾的低代谢防御策略

亮点 

•Repression of hepatic gluconeogenesis by labile heme drives malarial hypoglycemia

•Hypoglycemia lowers Plasmodium virulence

•Malarial hypoglycemia compromises host energy metabolism and thermoregulation

•Plasmodium undergoes gametocytogenesis in response to hypoglycemia

Graphical abstract

摘要

Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal outcome of Plasmodium falciparum infection. Here, we report that malaria-associated hypoglycemia emerges from a non-canonical resistance mechanism, whereby the infected host reduces glycemia to starve Plasmodium. This hypometabolic response is elicited by labile heme, a byproduct of hemolysis that induces illness-induced anorexia and represses hepatic glucose production. While transient repression of hepatic glucose production prevents unfettered immune-mediated inflammation, organ damage, and anemia, when sustained over time it leads to hypoglycemia, compromising host energy expenditure and adaptive thermoregulation. The latter arrests the development of asexual stages of Plasmodium via a mechanism associated with parasite mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program associated with the reduction of virulence and sexual differentiation toward the generation of transmissible gametocytes. In conclusion, malaria-associated hypoglycemia represents a trade-off of a hypometabolic-based defense strategy that balances parasite virulence versus transmission.

Keywords: evolutionary trade-off; heme; hypoglycemia; malaria; transmission; virulence.

关键词：进化权衡； 血红素； 低血糖症;  疟疾;  传播;  毒力。

参考资料：

原文 Ramos S, Ademolue TW, Jentho E, et al. A hypometabolic defense strategy against malaria. Cell Metab. 2022;34(8):1183-1200.e12. DOI: https://doi.org/10.1016/j.cmet.2022.06.011 

全文： https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00231-5