TNF and type I IFN induction of the IRG1-itaconate pathway restricts replication within mouse macrophages.

The intracellular Gram-negative bacterium replicates within macrophages and causes a zoonotic disease known as Q fever. In murine macrophages, the cytokine tumor necrosis factor (TNF) is critical for restriction of intracellular replication. Here, we show that TNF collaborates with type I interferon (IFN) signaling for maximal control of . We found that TNF and type I IFN upregulate the expression of the metabolic enzyme immune responsive gene 1 (IRG1), also known as cis-aconitate decarboxylase 1 (ACOD1), and that IRG1 is required to restrict T4SS translocation and replication within macrophages. Further, we show that itaconic acid, the metabolic product of IRG1, restricts replication both intracellularly and in axenic culture. These data reveal that TNF and type I IFN upregulate the IRG1-itaconate pathway to restrict intracellular replication within murine macrophages.