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Blood, 22 October 2009, Vol. 114, No. 17, pp. 3642-3651. Prepublished online as a Blood First Edition Paper on August 21, 2009; DOI 10.1182/blood-2009-05-223354. This Article Full Text Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2009-05-223354v1 114/17/3642    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Nairz, M. Articles by Weiss, G. PubMed PubMed Citation Articles by Nairz, M. Articles by Weiss, G. Related Collections Phagocytes, Granulocytes, and Myelopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS Absence of functional Hfe protects mice from invasive Salmonella enterica Serovar Typhimurium infection via induction of lipocalin-2 Manfred Nairz1, Igor Theurl1, Andrea Schroll1, Milan Theurl1,2, Gernot Fritsche1, Ewald Lindner1, Markus Seifert1, Marie-Laure V. Crouch3, Klaus Hantke4, Shizuo Akira5, Ferric C. Fang3,6, and Günter Weiss1 Departments of 1 Internal Medicine I, Clinical Immunology and Infectious Diseases, and 2 Ophthalmology, Medical University of Innsbruck, Innsbruck, Austria; 3 Department of Laboratory Medicine, University of Washington, Seattle; 4 Department of Microbiology/Membrane Physiology, University of Tübingen, Tübingen, Germany; 5 Department of Host Defense, Osaka University, and Exploratory Research for Advanced Technology (ERATO), Japan, and Science and Technology Corporation, Osaka, Japan; and 6 Department of Microbiology, University of Washington, Seattle Mutations of HFE are associated with hereditary hemochromatosis, but their influence on host susceptibility to infection is incompletely understood. We report that mice lacking one or both Hfe alleles are protected from septicemia with Salmonella Typhimurium, displaying prolonged survival and improved control of bacterial replication. This increased resistance is paralleled by an enhanced production of the enterochelin-binding peptide lipocalin-2 (Lcn2), which reduces the availability of iron for Salmonella within Hfe-deficient macrophages. Accordingly, Hfe–/–Lcn2–/– macrophages are unable to efficiently control the infection or to withhold iron from intracellular Salmonella. Correspondingly, the protection conferred by the Hfe defect is abolished in Hfe–/– mice infected with enterochelin-deficient Salmonella as well as in Hfe–/–Lcn2–/– mice infected with wild-type bacteria. Thus, by induction of the iron-capturing peptide Lcn2, absence of functional Hfe confers host resistance to systemic infection with Salmonella, thereby providing an evolutionary advantage which may account for the high prevalence of genetic hemochromatosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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