Absence of functional Hfe protects mice from invasive Salmonella enterica serovar Typhimurium infection via induction of lipocalin-2.
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.
Nairz
Manfred
M
Department of Internal Medicine I, Clinical Immunology and Infectious Diseases, Medical University of Innsbruck, Innsbruck, Austria.
Theurl
Igor
I
Schroll
Andrea
A
Theurl
Milan
M
Fritsche
Gernot
G
Lindner
Ewald
E
Seifert
Markus
M
Crouch
Marie-Laure V
ML
Hantke
Klaus
K
Akira
Shizuo
S
Fang
Ferric C
FC
Weiss
Günter
G
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*
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
J Immunol. 2008 Aug 15;181(4):2723-31
18684963
J Leukoc Biol. 2007 Jan;81(1):195-204
17038583
J Immunol. 2004 May 15;172(10):6202-8
15128808
Perspect Biol Med. 2008 Winter;51(1):98-102
18192769
Nat Genet. 2003 May;34(1):97-101
12704388
Nat Rev Mol Cell Biol. 2003 Feb;4(2):105-16
12563288
J Infect Dis. 1997 Jun;175(6):1467-76
9180188
Cell Metab. 2008 Feb;7(2):173-8
18249176
J Exp Med. 2000 Nov 6;192(9):1237-48
11067873
Cell. 1978 Jul;14(3):489-99
210954
Nat Genet. 1996 Aug;13(4):399-408
8696333
Immunol Lett. 2003 Jan 22;85(2):193-5
12527227
Blood. 2008 Feb 15;111(4):2392-9
18073346
Exp Hematol. 1992 Jun;20(5):605-10
1587306
Blood Cells Mol Dis. 2002 Nov-Dec;29(3):361-6
12547226
Blood. 1998 Feb 1;91(3):1059-66
9446669
Blood. 1998 Oct 1;92(7):2511-9
9746792
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3677-82
12655053
Lancet. 2003 Feb 22;361(9358):669-73
12606179
Infect Immun. 2003 Dec;71(12):6953-61
14638784
Cell. 2004 Apr 30;117(3):285-97
15109490
Nature. 1999 Oct 21;401(6755):804-8
10548107
Mol Microbiol. 2000 Mar;35(5):1146-55
10712695
Blood. 2007 Dec 1;110(12):4096-100
17724144
Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1324-8
15665091
J Exp Med. 1997 Feb 17;185(4):717-30
9034150
J Exp Med. 1994 Sep 1;180(3):969-76
7520477
J Leukoc Biol. 2008 Sep;84(3):689-700
18586980
J Leukoc Biol. 2001 Jan;69(1):43-9
11200066
Blood. 2008 Aug 1;112(3):866-74
18369153
N Engl J Med. 2004 Jun 3;350(23):2383-97
15175440
Blood. 1997 Apr 1;89(7):2546-53
9116301
Mol Biol Cell. 2007 Jul;18(7):2569-78
17475779
Cell Metab. 2009 Mar;9(3):217-27
19254567
Cell. 2005 Dec 29;123(7):1293-305
16377569
J Biol Chem. 2002 Oct 18;277(42):39786-91
12161425
J Biol Chem. 2002 Dec 20;277(51):49727-34
12399453
Hepatology. 2009 Mar;49(3):1012-6
19152427
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13312-7
10557317
Cell Microbiol. 2009 Sep;11(9):1365-81
19500110
J Leukoc Biol. 2003 Aug;74(2):287-94
12885946
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15602-7
12429850
Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1834-9
16446425
Nat Rev Microbiol. 2004 Dec;2(12):946-53
15550940
Eur J Immunol. 2008 Jul;38(7):1923-36
18581323
Science. 2004 Dec 17;306(5704):2090-3
15514116
Annu Rev Physiol. 2007;69:69-85
17014365
Nature. 2004 Dec 16;432(7019):917-21
15531878
Int J Biochem Cell Biol. 1999 Oct;31(10):991-4
10582331
Blood. 2005 Dec 1;106(12):3710-7
16030190
Blood. 2003 May 15;101(10):4148-54
12522003
Cell Microbiol. 2007 Sep;9(9):2126-40
17466014
Int J Hematol. 2002 Oct;76(3):203-7
12416729
J Clin Invest. 2007 Sep;117(9):2649-57
17786247
Mol Microbiol. 2008 Mar;67(5):971-83
18194158
N Engl J Med. 1996 Dec 12;335(24):1799-805
8943161