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

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. pseud...

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Published inThe Journal of clinical investigation Vol. 122; no. 6; pp. 2289 - 2300
Main Authors Tan, Kai Soo, Lee, Kok Onn, Low, Kee Chung, Gamage, Akshamal Mihiranga, Liu, Yichun, Tan, Gek-Yen Gladys, Koh, Hui Qi Vanessa, Alonso, Sylvie, Gan, Yunn-Hwen
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LanguageEnglish
Published United States American Society for Clinical Investigation 01.06.2012
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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.
AbstractList 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.
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 dia-betic patients were impaired in IL-12p70 production, which resulted in decreased IFN-γ induction and poor bac-terial 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.
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 unpaired 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. [PUBLICATION 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.
Audience Academic
Author Low, Kee Chung
Liu, Yichun
Koh, Hui Qi Vanessa
Alonso, Sylvie
Gamage, Akshamal Mihiranga
Tan, Gek-Yen Gladys
Tan, Kai Soo
Lee, Kok Onn
Gan, Yunn-Hwen
AuthorAffiliation 1 Department of Biochemistry and 2 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 3 Defence Medical and Environmental Research Institute, Defence Science Organization National Laboratories, Singapore. 4 Department of Microbiology, Yong Loo Lin School of Medicine, and 5 Immunology Program, National University of Singapore, Singapore
AuthorAffiliation_xml – name: 1 Department of Biochemistry and 2 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 3 Defence Medical and Environmental Research Institute, Defence Science Organization National Laboratories, Singapore. 4 Department of Microbiology, Yong Loo Lin School of Medicine, and 5 Immunology Program, National University of Singapore, Singapore
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  organization: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/22546856$$D View this record in MEDLINE/PubMed
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Snippet Individuals with type 2 diabetes are at increased risk of acquiring melioidosis, a disease caused by Burkholderia pseudomallei infection. Although up to half...
Individuals with type 2 diabetes are at increased risk of acquiring melioidosis, a disease caused by Burkholderia pseudomallei infection. Although up to half...
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SubjectTerms Adult
Aged
Animals
Antibiotics
Bacteria
Bacterial infections
Biomedical research
Burkholderia pseudomallei
Care and treatment
Cytokines
Diabetes
Diabetes Complications - metabolism
Diabetes Complications - microbiology
Diabetes Mellitus, Type 2 - metabolism
Diabetes Mellitus, Type 2 - microbiology
Diabetes Mellitus, Type 2 - pathology
Diagnosis
Disease
Disease Susceptibility - etiology
Disease Susceptibility - metabolism
Disease Susceptibility - microbiology
Disease Susceptibility - pathology
Female
Glutathione
Glutathione - deficiency
Health aspects
Humans
Infections
Interferon-gamma - metabolism
Interleukin-12 - metabolism
Leukocytes, Mononuclear - metabolism
Leukocytes, Mononuclear - microbiology
Male
Melioidosis - etiology
Melioidosis - metabolism
Melioidosis - microbiology
Melioidosis - pathology
Mice
Neutrophils
Physiological aspects
Properties
Salmonella enterica
Salmonella Infections - etiology
Salmonella Infections - metabolism
Salmonella Infections - pathology
Toll-Like Receptors - metabolism
Tuberculosis
Type 2 diabetes
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Title Glutathione deficiency in type 2 diabetes impairs cytokine responses and control of intracellular bacteria
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