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Individuals with type 2 diabetes are at increased risk of acquiring melioidosis,a disease caused by Burkholderia pseudomallei infection. Although up to half ofmelioidosis patients have underlying diabetes, the mechanisms involved in this increasedsusceptibility are unknown. We found that B. pseudomallei-infected PBMCsfrom diabetic patients were impaired in IL-12p70 production, which resulted in decreasedIFN-γ induction and poor bacterial killing. The defect was specific to theIL-12-IFN-γ axis. Defective IL-12 production was also observedduring Mycobacterium tuberculosis infection, in which diabetes is likewise known to be astrong risk factor. In contrast, IL-12 production in diabetic cells was not affectedupon Salmonella enterica infection or in response to TLR2, -3, -4, and -5 ligands. PoorIL-12 production correlated with a deficiency in intracellular reduced glutathione (GSH)concentrations in diabetic patients. Addition of GSH or N-acetylcysteine to PBMCsselectively restored IL-12 and IFN-γ production and improved bacterialkilling. Furthermore, the depletion of GSH in mice led to increased susceptibility tomelioidosis, reduced production of IL-12p70, and poorer disease outcome. Our data thusestablish a link between GSH deficiency in diabetes and increased susceptibility tomelioidosis that may open up new therapeutic avenues to protect diabetic patientsagainst some intracellular bacterial pathogens.

Glutathione deficiency in type 2 diabetes impairs cytokine responses and control of intracellular bacteria