Itaconate is an effector of a Rab GTPase cell-autonomous host defense pathway against <i>Salmonella</i>.

Abstract

The guanosine triphosphatase (GTPase) Rab32 coordinates a cell-intrinsic host defense mechanism that restricts the replication of intravacuolar pathogens such as <i>Salmonella</i> Here, we show that this mechanism requires aconitate decarboxylase 1 (IRG1), which synthesizes itaconate, a metabolite with antimicrobial activity. We find that Rab32 interacts with IRG1 on <i>Salmonella</i> infection and facilitates the delivery of itaconate to the <i>Salmonella</i>-containing vacuole. Mice defective in IRG1 rescued the virulence defect of a <i>S. enterica</i> serovar Typhimurium mutant specifically defective in its ability to counter the Rab32 defense mechanism. These studies provide a link between a metabolite produced in the mitochondria after stimulation of innate immune receptors and a cell-autonomous defense mechanism that restricts the replication of an intracellular bacterial pathogen.