Temporal multi-tissue profiling reveals metabolites linked to immune response and malaria parasitemia control

Malaria causes significant metabolic changes and cytokine production in the patient. The effects of species- and strain-specific immunity, as well as metabolic disorders, on malaria severity remain poorly understood. Here, we infected C57BL/6n mice with four <i>P. yoelii</i> strains and <i>P. berghei</i> ANKA (PbA), collected blood, spleen, and liver tissue samples on days 4 and 6 post-infection, and measured metabolite levels using LC-MS/MS. Tissue- and strain-specific metabolic alterations in glycolysis intermediates, amino acids, and nucleotides were identified and correlated with cytokine levels and parasitemia. Glycolysis intermediates, including bisphosphoglycerate, phosphoenolpyruvate, and dihydroxyacetone phosphate, were negatively correlated with parasitemia, suggesting consumption and lipid synthesis in the parasite apicoplast. Supplementing PbA-infected mice with depleted metabolites such as uridine significantly reduced parasitemia and MCP-1. Uridine supplementation also lowered <i>P. falciparum</i> parasitemia <i>in vitro</i>. These findings highlight uridine's potential as a supplement to modulate parasite growth, suggesting that metabolic interventions could enhance malaria treatment strategies.