title: Absence of functional Hfe protects mice from invasive Salmonella enterica serovar Typhimurium infection via induction of lipocalin-2.
abstract: 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.
authors.affiliation: Department of Internal Medicine I, Clinical Immunology and Infectious Diseases, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.forename: Andrea
authors.initials: A
authors.lastname: Schroll
authors.forename: Milan
authors.initials: M
authors.lastname: Theurl
authors.forename: Gernot
authors.initials: G
authors.lastname: Fritsche
authors.forename: Ewald
authors.initials: E
authors.lastname: Lindner
authors.forename: Markus
authors.initials: M
authors.lastname: Seifert
authors.forename: Marie-Laure V
authors.initials: ML
authors.lastname: Crouch
authors.forename: Klaus
authors.initials: K
authors.lastname: Hantke
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Ferric C
authors.initials: FC
authors.lastname: Fang
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D007501:Iron / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009573:Nitrites / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D012486:Salmonella typhimurium / Q000502:physiology*
chemical_list: D000209:Acute-Phase Proteins; D001426:Bacterial Proteins; D016207:Cytokines; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D000071068:Lipocalin-2; D054834:Lipocalins; D008565:Membrane Proteins; D009573:Nitrites; D015513:Oncogene Proteins; D017382:Reactive Oxygen Species; C071332:Lcn2 protein, mouse; D007501:Iron
references.citation: J Immunol. 2008 Aug 15;181(4):2723-31
references.pmid: 18684963
references.citation: J Leukoc Biol. 2007 Jan;81(1):195-204
references.pmid: 17038583
references.citation: J Immunol. 2004 May 15;172(10):6202-8
references.pmid: 15128808
references.citation: Perspect Biol Med. 2008 Winter;51(1):98-102
references.pmid: 18192769
references.citation: Nat Genet. 2003 May;34(1):97-101
references.pmid: 12704388
references.citation: Nat Rev Mol Cell Biol. 2003 Feb;4(2):105-16
references.pmid: 12563288
references.citation: J Infect Dis. 1997 Jun;175(6):1467-76
references.pmid: 9180188
references.citation: Cell Metab. 2008 Feb;7(2):173-8
references.pmid: 18249176
references.citation: J Exp Med. 2000 Nov 6;192(9):1237-48
references.pmid: 11067873
references.citation: Cell. 1978 Jul;14(3):489-99
references.pmid: 210954
references.citation: Nat Genet. 1996 Aug;13(4):399-408
references.pmid: 8696333
references.citation: Immunol Lett. 2003 Jan 22;85(2):193-5
references.pmid: 12527227
references.citation: Blood. 2008 Feb 15;111(4):2392-9
references.pmid: 18073346
references.citation: Exp Hematol. 1992 Jun;20(5):605-10
references.pmid: 1587306
references.citation: Blood Cells Mol Dis. 2002 Nov-Dec;29(3):361-6
references.pmid: 12547226
references.citation: Blood. 1998 Feb 1;91(3):1059-66
references.pmid: 9446669
references.citation: Blood. 1998 Oct 1;92(7):2511-9
references.pmid: 9746792
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3677-82
references.pmid: 12655053
references.citation: Lancet. 2003 Feb 22;361(9358):669-73
references.pmid: 12606179
references.citation: Infect Immun. 2003 Dec;71(12):6953-61
references.pmid: 14638784
references.citation: Cell. 2004 Apr 30;117(3):285-97
references.pmid: 15109490
references.citation: Nature. 1999 Oct 21;401(6755):804-8
references.pmid: 10548107
references.citation: Mol Microbiol. 2000 Mar;35(5):1146-55
references.pmid: 10712695
references.citation: Blood. 2007 Dec 1;110(12):4096-100
references.pmid: 17724144
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1324-8
references.pmid: 15665091
references.citation: J Exp Med. 1997 Feb 17;185(4):717-30
references.pmid: 9034150
references.citation: J Exp Med. 1994 Sep 1;180(3):969-76
references.pmid: 7520477
references.citation: J Leukoc Biol. 2008 Sep;84(3):689-700
references.pmid: 18586980
references.citation: J Leukoc Biol. 2001 Jan;69(1):43-9
references.pmid: 11200066
references.citation: Blood. 2008 Aug 1;112(3):866-74
references.pmid: 18369153
references.citation: N Engl J Med. 2004 Jun 3;350(23):2383-97
references.pmid: 15175440
references.citation: Blood. 1997 Apr 1;89(7):2546-53
references.pmid: 9116301
references.citation: Mol Biol Cell. 2007 Jul;18(7):2569-78
references.pmid: 17475779
references.citation: Cell Metab. 2009 Mar;9(3):217-27
references.pmid: 19254567
references.citation: Cell. 2005 Dec 29;123(7):1293-305
references.pmid: 16377569
references.citation: J Biol Chem. 2002 Oct 18;277(42):39786-91
references.pmid: 12161425
references.citation: J Biol Chem. 2002 Dec 20;277(51):49727-34
references.pmid: 12399453
references.citation: Hepatology. 2009 Mar;49(3):1012-6
references.pmid: 19152427
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13312-7
references.pmid: 10557317
references.citation: Cell Microbiol. 2009 Sep;11(9):1365-81
references.pmid: 19500110
references.citation: J Leukoc Biol. 2003 Aug;74(2):287-94
references.pmid: 12885946
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15602-7
references.pmid: 12429850
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1834-9
references.pmid: 16446425
references.citation: Nat Rev Microbiol. 2004 Dec;2(12):946-53
references.pmid: 15550940
references.citation: Eur J Immunol. 2008 Jul;38(7):1923-36
references.pmid: 18581323
references.citation: Science. 2004 Dec 17;306(5704):2090-3
references.pmid: 15514116
references.citation: Annu Rev Physiol. 2007;69:69-85
references.pmid: 17014365
references.citation: Nature. 2004 Dec 16;432(7019):917-21
references.pmid: 15531878
references.citation: Int J Biochem Cell Biol. 1999 Oct;31(10):991-4
references.pmid: 10582331
references.citation: Blood. 2005 Dec 1;106(12):3710-7
references.pmid: 16030190
references.citation: Blood. 2003 May 15;101(10):4148-54
references.pmid: 12522003
references.citation: Cell Microbiol. 2007 Sep;9(9):2126-40
references.pmid: 17466014
references.citation: Int J Hematol. 2002 Oct;76(3):203-7
references.pmid: 12416729
references.citation: J Clin Invest. 2007 Sep;117(9):2649-57
references.pmid: 17786247
references.citation: Mol Microbiol. 2008 Mar;67(5):971-83
references.pmid: 18194158
references.citation: N Engl J Med. 1996 Dec 12;335(24):1799-805
references.pmid: 8943161