Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Instituto Gulbenkian de Ciência, Oeiras, Portugal; Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany.
Cell Metab. 2022 Aug 2;34(8):1183-1200.e12. doi: 10.1016/j.cmet.2022.06.011. Epub 2022 Jul 15.
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.
低血糖是严重疟疾的一个临床特征，是恶性疟原虫感染的常见致死性后果。在这里，我们报告说，疟疾相关的低血糖是由一种非经典的耐药机制引起的，即受感染的宿主通过降低血糖来饿死疟原虫。这种低代谢反应是由不稳定的血红素引起的，血红素是溶血的副产物，它会引起疾病引起的厌食和抑制肝葡萄糖生成。虽然短暂抑制肝葡萄糖生成可以防止不受限制的免疫介导的炎症、器官损伤和贫血，但如果持续时间过长，它会导致低血糖，从而损害宿主的能量消耗和适应性体温调节。后者通过与寄生虫线粒体功能障碍相关的机制阻止了疟原虫无性阶段的发育。作为回应，疟原虫激活了一个与降低毒力和向可传播配子体分化相关的转录程序。总之，疟疾相关的低血糖代表了一种基于低代谢的防御策略的权衡，该策略平衡了寄生虫的毒力与传播。
