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Cell Host Microbe. 2015 Aug 12;18(2):254-61. doi: 10.1016/j.chom.2015.06.017. Epub 2015 Jul 16.

Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection.

Author information

1
Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, and Pneumology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
2
European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
3
Department of Laboratory Medicine, University of Washington, Seattle, WA 98195-7735, USA; Department of Microbiology, University of Washington, Seattle, WA 98195-7735, USA.
4
European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany. Electronic address: hentze@embl.de.
5
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.

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.

PMID:
26190773
PMCID:
PMC4666941
DOI:
10.1016/j.chom.2015.06.017
[Indexed for MEDLINE]
Free PMC Article
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