Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection

• Published in: Cell host & microbe 2015-08, Vol.18 (2), p.254-261
• Main Authors: Nairz, Manfred, Ferring-Appel, Dunja, Casarrubea, Daniela, Sonnweber, Thomas, Viatte, Lydie, Schroll, Andrea, Haschka, David, Fang, Ferric C., Hentze, Matthias W., Weiss, Guenter, Galy, Bruno
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Load; Disease Models, Animal; Disease Resistance; Gene Knockout Techniques; Iron - metabolism; Iron Regulatory Protein 1 - genetics; Iron Regulatory Protein 1 - metabolism; Iron Regulatory Protein 2 - genetics; Iron Regulatory Protein 2 - metabolism; Liver - microbiology; Macrophages - immunology; Macrophages - microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Salmonella Infections, Animal - immunology; Salmonella typhimurium - immunology; Spleen - microbiology
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2015.06.017

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. [Display omitted] •IRPs control key molecules of iron sequestration and transport in macrophages•Macrophage IRP function is dispensable for maintaining steady-state body iron balance•Macrophage IRPs protect mice against infection with Salmonella Typhimurium•IRPs restrict intracellular Salmonella growth by at least two mechanisms Pathogens require iron to proliferate in vivo. Nairz and Ferring-Appel et al. show that macrophage-specific ablation of iron regulatory proteins 1 and 2, RNA-binding factors that orchestrate mammalian iron metabolism, impairs innate immunity against Salmonella in mice, in part due to failure of the host to limit microbial iron acquisition.