title: Elucidation of the mechanism by which catecholamine stress hormones liberate iron from the innate immune defense proteins transferrin and lactoferrin.
abstract: The ability of catecholamine stress hormones and inotropes to stimulate the growth of infectious bacteria is now well established. A major element of the growth induction process has been shown to involve the catecholamines binding to the high-affinity ferric-iron-binding proteins transferrin (Tf) and lactoferrin, which then enables bacterial acquisition of normally inaccessible sequestered host iron. The nature of the mechanism(s) by which the stress hormones perturb iron binding of these key innate immune defense proteins has not been fully elucidated. The present study employed electron paramagnetic resonance spectroscopy and chemical iron-binding analyses to demonstrate that catecholamine stress hormones form direct complexes with the ferric iron within transferrin and lactoferrin. Moreover, these complexes were shown to result in the reduction of Fe(III) to Fe(II) and the loss of protein-complexed iron. The use of bacterial ferric iron uptake mutants further showed that both the Fe(II) and Fe(III) released from the Tf could be directly used as bacterial nutrient sources. We also analyzed the transferrin-catecholamine interactions in human serum and found that therapeutically relevant concentrations of stress hormones and inotropes could directly affect the iron binding of serum-transferrin so that the normally highly bacteriostatic tissue fluid became significantly more supportive of the growth of bacteria. The relevance of these catecholamine-transferrin/lactoferrin interactions to the infectious disease process is considered.
authors.affiliation: Department of Infection, University of Leicester, Leicester, UK.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Sandrini
authors.forename: Raminder
authors.initials: R
authors.lastname: Shergill
authors.forename: Jonathan
authors.initials: J
authors.lastname: Woodward
authors.forename: Remya
authors.initials: R
authors.lastname: Muralikuttan
authors.forename: Richard D
authors.initials: RD
authors.lastname: Haigh
authors.forename: Mark
authors.initials: M
authors.lastname: Lyte
authors.forename: Primrose P
authors.initials: PP
authors.lastname: Freestone
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D002395:Catecholamines / Q000737:chemistry / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D004926:Escherichia coli / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D007501:Iron / Q000378:metabolism*; D007781:Lactoferrin / Q000378:metabolism*; D015394:Molecular Structure; D009638:Norepinephrine / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D014168:Transferrin / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D002395:Catecholamines; D014168:Transferrin; D007501:Iron; D007781:Lactoferrin; D009638:Norepinephrine