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临床标志，是恶性疟原虫感染的致命后果。在这里，我们报告了与疟疾相关的低血糖症源于一种非典型的抗性机制，即受感染的宿主会降低血糖症以使疟原虫饿死。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品，可诱导疾病引起的厌食并抑制肝葡萄糖的产生。虽然对肝葡萄糖产生的短暂抑制可防止不受约束的免疫介导的炎症、器官损伤和贫血，但随着时间的推移，它会导致低血糖，损害宿主能量消耗和适应性体温调节。后者阻止了疟原虫无性阶段的发展通过与寄生虫线粒体功能障碍相关的机制。作为响应，疟原虫激活了一个转录程序，该程序与减少毒力和性分化以产生可传播的配子体有关。总之，与疟疾相关的低血糖症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。