title: Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection.
abstract: Macrophages are essential for systemic iron recycling, and also control iron availability to pathogens. Iron metabolism in mammalian cells is orchestrated posttranscriptionally by iron-regulatory proteins (IRP)-1 and -2. Here, we generated mice with selective and combined ablation of both IRPs in macrophages to investigate the role of IRPs in controlling iron availability. These animals are hyperferritinemic but otherwise display normal clinical iron parameters. However, mutant mice rapidly succumb to systemic infection with Salmonella Typhimurium, a pathogenic bacterium that multiplies within macrophages, with increased bacterial burdens in liver and spleen. Ex vivo infection experiments indicate that IRP function restricts bacterial access to iron via the EntC and Feo bacterial iron-acquisition systems. Further, IRPs contain Salmonella by promoting the induction of lipocalin 2, a host antimicrobial factor that inhibits bacterial uptake of iron-laden siderophores, and by suppressing the ferritin iron pool. This work reveals the importance of the IRPs in innate immunity.
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, and Pneumology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Dunja
authors.initials: D
authors.lastname: Ferring-Appel
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Casarrubea
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, and Pneumology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sonnweber
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Lydie
authors.initials: L
authors.lastname: Viatte
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, and Pneumology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schroll
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, and Pneumology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Haschka
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA 98195-7735, USA; Department of Microbiology, University of Washington, Seattle, WA 98195-7735, USA.
authors.forename: Ferric C
authors.initials: FC
authors.lastname: Fang
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany. Electronic address: hentze@embl.de.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Hentze
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, and Pneumology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. Electronic address: guenter.weiss@i-med.ac.at.
authors.forename: Guenter
authors.initials: G
authors.lastname: Weiss
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Galy
mesh_terms: D000818:Animals; D058491:Bacterial Load; D004195:Disease Models, Animal; D060467:Disease Resistance; D055786:Gene Knockout Techniques; D007501:Iron / Q000378:metabolism; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012481:Salmonella Infections, Animal / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*; D013154:Spleen / Q000382:microbiology
chemical_list: D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2