A hypometabolic defense strategy against malaria

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. [Display omitted] •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 Malaria-associated hypoglycemia develops as a trade-off of a non-canonical resistance mechanism against Plasmodium infection based on restricting parasite access to glucose. In response, Plasmodium reduces its virulence in favor of transmission, an evolutionarily conserved host-pathogen cooperative metabolic behavior.