TNF and type I IFN induction of the IRG1-itaconate pathway restrictsCoxiella burnetiireplication within mouse macrophages

Abstract

AbstractThe intracellular Gram-negative bacteriumCoxiella burnetiireplicates 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 intracellularC. burnetiireplication. Here, we show that TNF collaborates with type I interferon (IFN) signaling for maximal control ofC. burnetii. 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 restrictC. burnetiiT4SS translocation and replication within macrophages. Further, we show that itaconic acid, the metabolic product of IRG1, restrictsC. burnetiireplication both intracellularly and in axenic culture. These data reveal that TNF and type I IFN upregulate the IRG1-itaconate pathway to restrict intracellularC.burnetiireplication within murine macrophages.