Itaconate Has Limited Protective Effects in Experimental Malaria Models

In severe malaria, dysregulated metabolism and excessive inflammatory responses contribute to fatal outcomes. Therapeutic strategies that address both metabolic and inflammatory balances are thus required. Itaconate, a metabolite produced by aconitate decarboxylase 1 (ACOD1), is a potent inhibitor of both inflammation and glycolysis with protective effects in various inflammatory diseases. Although elevated itaconate levels have been observed in Plasmodium-infected individuals, its role in malaria is still poorly understood, making further investigation essential for assessing its therapeutic potential. We investigated the role of itaconate in both severe and mild malaria using Plasmodium berghei NK65 (PbNK65) and Plasmodium chabaudi AS (PcAS) models, respectively. Using ¹³C-tracer metabolomics, we detected increased itaconate levels in various organs during infection and identified inflammatory monocytes as the source of this production. Nevertheless, ACOD1 knockout mice displayed no significant changes in phenotype after PbNK65 infection, and treatment of PbNK65-infected mice with 4-octyl itaconate did not affect disease severity either. However, in the PcAS model, ACOD1 deficiency worsened the disease, as indicated by increased weight loss, higher clinical scores, and elevated parasitemia. Therefore, in contrast to the findings in recent literature, our study shows that itaconate does not contribute to susceptibility, but rather provides limited protection to malaria.