title: Glutathione reductase is essential for host defense against bacterial infection.
abstract: Glutathione reductase (Gsr) catalyzes the reduction of glutathione disulfide to glutathione, a major cellular antioxidant. We have recently shown that Gsr is essential for host defense against the gram-negative bacteria Escherichia coli in a mouse model of sepsis. Although we have demonstrated that Gsr is required for sustaining the oxidative burst and the development of neutrophil extracellular traps, the role of Gsr in other phagocytic functions remains unclear. It is also unclear whether Gsr-deficient mice exhibit host defense defects against gram-positive bacteria. In this study, we characterized the effects of Gsr deficiency on the innate immune responses to a gram-positive bacterium, group B Streptococcus, and to the gram-negative bacterial cell wall component lipopolysaccharide (LPS). We found that, like E. coli, group B Streptococcus resulted in a substantially more robust cytokine response and a markedly higher morbidity and mortality in Gsr-deficient mice than in wild-type mice. The increased morbidity and mortality were associated with greater bacterial burden in the Gsr-deficient mice. Interestingly, Gsr-deficient mice did not exhibit a greater sensitivity to LPS than did wild-type mice. Analysis of the neutrophils of Gsr-deficient mice revealed impaired phagocytosis. In response to thioglycollate stimulation, Gsr-deficient mice mobilized far fewer phagocytes, including neutrophils, macrophages, and eosinophils, into their peritoneal cavities than did wild-type mice. The defective phagocyte mobilization is associated with profound oxidation and aggregation of ascitic proteins, particularly albumin. Our results indicate that the oxidative defense mechanism mediated by Gsr is required for an effective innate immune response against bacteria, probably by preventing phagocyte dysfunction due to oxidative damage.
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA; State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yan
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Ralston
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Meng
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Bongiovanni
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Jones
authors.affiliation: Center for Translational Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
authors.forename: Rainer
authors.initials: R
authors.lastname: Benndorf
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
authors.forename: Leif D
authors.initials: LD
authors.lastname: Nelin
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
authors.forename: W
authors.initials: W
authors.lastname: Joshua Frazier
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
authors.forename: Lynette K
authors.initials: LK
authors.lastname: Rogers
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Charles V
authors.initials: CV
authors.lastname: Smith
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA. Electronic address: yusen.liu@nationwidechildrens.org.
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D002465:Cell Movement; D004731:Endotoxins / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000502:physiology*; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D010587:Phagocytosis; D013290:Streptococcal Infections / Q000276:immunology / Q000401:mortality; D013292:Streptococcus agalactiae
chemical_list: D004731:Endotoxins; D005980:Glutathione Reductase; D005978:Glutathione
keywords: Animal model; Bacterial infection; Free radicals; Group B Streptococcus; Host defense; Oxidative burst; Phagocytes; Redox regulation