A hypometabolic defense strategy against malaria

Susana Ramos, Temitope W Ademolue, Elisa Jentho, Qian Wu, Joel Guerra, Rui Martins, Gil Pires, Sebastian Weis, Ana Rita Carlos, Inês Mahú, Elsa Seixas, Denise Duarte, Fabienne Rajas, Sílvia Cardoso, António G G Sousa, Jingtao Lilue, Tiago Paixão, Gilles Mithieux, Fátima Nogueira, Miguel P Soares

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Abstract

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.

Original languageEnglish
JournalCell Metabolism
DOIs
Publication statusE-pub ahead of print - 7 Jul 2022

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