title: Glutathione deficiency in type 2 diabetes impairs cytokine responses and             control of intracellular bacteria.
abstract: Individuals with type 2 diabetes are at increased risk of acquiring melioidosis,             a disease caused by Burkholderia pseudomallei infection. Although up to half of             melioidosis patients have underlying diabetes, the mechanisms involved in this increased             susceptibility are unknown. We found that B. pseudomallei-infected PBMCs             from diabetic patients were impaired in IL-12p70 production, which resulted in decreased             IFN-γ induction and poor bacterial killing. The defect was specific to the             IL-12-IFN-γ axis. Defective IL-12 production was also observed             during Mycobacterium tuberculosis infection, in which diabetes is likewise known to be a             strong risk factor. In contrast, IL-12 production in diabetic cells was not affected             upon Salmonella enterica infection or in response to TLR2, -3, -4, and -5 ligands. Poor             IL-12 production correlated with a deficiency in intracellular reduced glutathione (GSH)             concentrations in diabetic patients. Addition of GSH or N-acetylcysteine to PBMCs             selectively restored IL-12 and IFN-γ production and improved bacterial             killing. Furthermore, the depletion of GSH in mice led to increased susceptibility to             melioidosis, reduced production of IL-12p70, and poorer disease outcome. Our data thus             establish a link between GSH deficiency in diabetes and increased susceptibility to             melioidosis that may open up new therapeutic avenues to protect diabetic patients             against some intracellular bacterial pathogens.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Kai Soo
authors.initials: KS
authors.lastname: Tan
authors.forename: Kok Onn
authors.initials: KO
authors.lastname: Lee
authors.forename: Kee Chung
authors.initials: KC
authors.lastname: Low
authors.forename: Akshamal Mihiranga
authors.initials: AM
authors.lastname: Gamage
authors.forename: Yichun
authors.initials: Y
authors.lastname: Liu
authors.forename: Gek-Yen Gladys
authors.initials: GY
authors.lastname: Tan
authors.forename: Hui Qi Vanessa
authors.initials: HQ
authors.lastname: Koh
authors.forename: Sylvie
authors.initials: S
authors.lastname: Alonso
authors.forename: Yunn-Hwen
authors.initials: YH
authors.lastname: Gan
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016957:Burkholderia pseudomallei; D048909:Diabetes Complications / Q000378:metabolism* / Q000382:microbiology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D004198:Disease Susceptibility / Q000209:etiology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D005260:Female; D005978:Glutathione / Q000172:deficiency*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000382:microbiology; D008297:Male; D008554:Melioidosis / Q000209:etiology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D012480:Salmonella Infections / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D019779:Salmonella enterica; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D051193:Toll-Like Receptors; D018664:Interleukin-12; D007371:Interferon-gamma; D005978:Glutathione