title: Adaptation of iron homeostasis pathways by a Pseudomonas aeruginosa pyoverdine mutant in the cystic fibrosis lung.
abstract: Cystic fibrosis (CF) patients suffer from chronic bacterial lung infections, most notably by Pseudomonas aeruginosa, which persists for decades in the lungs and undergoes extensive evolution. P. aeruginosa requires iron for virulence and uses the fluorescent siderophore pyoverdine to scavenge and solubilize ferric iron during acute infections. Pyoverdine mutants accumulate in the lungs of some CF patients, however, suggesting that the heme and ferrous iron acquisition pathways of P. aeruginosa are more important in this environment. Here, we sought to determine how evolution of P. aeruginosa in the CF lung affects iron acquisition and regulatory pathways through the use of longitudinal CF isolates. These analyses demonstrated a significant reduction of siderophore production during the course of CF lung infection in nearly all strains tested. Mass spectrometry analysis of one of these strains showed that the later CF isolate has streamlined the metabolic flux of extracellular heme through the HemO heme oxygenase, resulting in more-efficient heme utilization. Moreover, gene expression analysis shows that iron regulation via the PrrF small RNAs (sRNAs) is enhanced in the later CF isolate. Finally, analysis of P. aeruginosa gene expression in the lungs of various CF patients demonstrates that both PrrF and HemO are consistently expressed in the CF lung environment. Combined, these results suggest that heme is a critical source of iron during prolonged infection of the CF lung and that changes in iron and heme regulatory pathways play a crucial role in adaptation of P. aeruginosa to this ever-changing host environment.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Angela T
authors.initials: AT
authors.lastname: Nguyen
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Maura J
authors.initials: MJ
authors.lastname: O'Neill
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Annabelle M
authors.initials: AM
authors.lastname: Watts
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Robson
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Iain L
authors.initials: IL
authors.lastname: Lamont
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Wilks
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland, USA aoglesby@rx.umaryland.edu.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Oglesby-Sherrouse
mesh_terms: D000222:Adaptation, Physiological; D000293:Adolescent; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000382:microbiology*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D009154:Mutation; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism*; D010860:Pigments, Biological; D011552:Pseudomonas Infections / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D001426:Bacterial Proteins; D009842:Oligopeptides; D010860:Pigments, Biological; C042453:pyoverdin; D007501:Iron
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