title: Interplay between enterobactin, myeloperoxidase and lipocalin 2 regulates E. coli survival in the inflamed gut.
abstract: During an inflammatory response in the gut, some commensal bacteria such as E. coli can thrive and contribute to disease. Here we demonstrate that enterobactin (Ent), a catecholate siderophore released by E. coli, is a potent inhibitor of myeloperoxidase (MPO), a bactericidal enzyme of the host. Glycosylated Ent (salmochelin) and non-catecholate siderophores (yersiniabactin and ferrichrome) fail to inhibit MPO activity. An E. coli mutant (ΔfepA) that overproduces Ent, but not an Ent-deficient double mutant (ΔaroB/ΔfepA), inhibits MPO activity and exhibits enhanced survival in inflamed guts. This survival advantage is counter-regulated by lipocalin 2, a siderophore-binding host protein, which rescues MPO from Ent-mediated inhibition. Spectral analysis reveals that Ent interferes with compound I [oxoiron, Fe(IV)=O] and reverts the enzyme back to its native ferric [Fe(III)] state. These findings define a fundamental mechanism by which E. coli surpasses the host innate immune responses during inflammatory gut diseases and gains a distinct survival advantage.
authors.affiliation: Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Beng San
authors.initials: BS
authors.lastname: Yeoh
authors.affiliation: Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109-5602, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bachman
authors.affiliation: Department of Hematology, The Granulocyte Research Laboratory, National University Hospital, University of Copenhagen, Copenhagen 2100, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Borregaard
authors.affiliation: Department of Physiology and Pharmacology, Center for Hypertension and Personalized Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, USA.
authors.forename: Bina
authors.initials: B
authors.lastname: Joe
authors.affiliation: 1] Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, USA [2] Department of Medicine, Pennsylvania State University Medical Center, Hershey, Pennsylvania 17033, USA.
authors.forename: Matam
authors.initials: M
authors.lastname: Vijay-Kumar
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003092:Colitis / Q000139:chemically induced; D016264:Dextran Sulfate / Q000633:toxicity; D004758:Enterobactin / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation / Q000139:chemically induced* / Q000382:microbiology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; C071332:Lcn2 protein, mouse; D004758:Enterobactin; D016264:Dextran Sulfate; D009195:Peroxidase