Toll-like receptor (TLR) stimulation induces a pronounced shift to increased glycolytic metabolism in mammalian macrophages. We observed that bone marrow-derived macrophages (BMMs) increase glycolysis in response to infection with , but the role of host macrophage glycolysis in terms of intracellular replication is not currently understood. Treatment with 2-deoxyglucose (2DG) blocks replication in mammalian macrophages but has no effect on bacteria grown in broth. In addition, we found that 2DG had no effect on bacteria grown in amoebae. We used a serial enrichment strategy to reveal that the effect of 2DG on in macrophages requires the hexose-phosphate transporter UhpC. Experiments with UhpC-deficient revealed that mutant bacteria are also resistant to growth inhibition following treatment with phosphorylated 2DG in broth, suggesting that the inhibitory effect of 2DG on in mammalian cells requires 2DG phosphorylation. UhpC-deficient replicates without a growth defect in BMMs and protozoan host cells and also replicates without a growth defect in BMMs treated with 2DG. Our data indicate that neither TLR signaling-dependent increased macrophage glycolysis nor inhibition of macrophage glycolysis has a substantial effect on intracellular replication. These results are consistent with the view that can employ diverse metabolic strategies to exploit its host cells. We explored the relationship between macrophage glycolysis and replication of an intracellular bacterial pathogen, Previous studies demonstrated that a glycolysis inhibitor, 2-deoxyglucose (2DG), blocks replication of during infection of macrophages, leading to speculation that may exploit macrophage glycolysis. We isolated mutants resistant to the inhibitory effect of 2DG in macrophages, identifying a hexose-phosphate transporter, UhpC, that is required for bacterial sensitivity to 2DG during infection. Our results reveal how a bacterial transporter mediates the direct antimicrobial effect of a toxic metabolite. Moreover, our results indicate that neither induction nor impairment of host glycolysis inhibits intracellular replication of, which is consistent with a view of as a metabolic generalist.
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