Histidine-rich glycoprotein protects from systemic Candida infection.
Fungi, such as Candida spp., are commonly found on the skin and at mucosal surfaces. Yet, they rarely cause invasive infections in immunocompetent individuals, an observation reflecting the ability of our innate immune system to control potentially invasive microbes found at biological boundaries. Antimicrobial proteins and peptides are becoming increasingly recognized as important effectors of innate immunity. This is illustrated further by the present investigation, demonstrating a novel antifungal role of histidine-rich glycoprotein (HRG), an abundant and multimodular plasma protein. HRG bound to Candida cells, and induced breaks in the cell walls of the organisms. Correspondingly, HRG preferentially lysed ergosterol-containing liposomes but not cholesterol-containing ones, indicating a specificity for fungal versus other types of eukaryotic membranes. Both antifungal and membrane-rupturing activities of HRG were enhanced at low pH, and mapped to the histidine-rich region of the protein. Ex vivo, HRG-containing plasma as well as fibrin clots exerted antifungal effects. In vivo, Hrg(-/-) mice were susceptible to infection by C. albicans, in contrast to wild-type mice, which were highly resistant to infection. The results demonstrate a key and previously unknown antifungal role of HRG in innate immunity.
Rydengård
Victoria
V
Section of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden. victoria.rydengard@med.lu.se
Shannon
Oonagh
O
Lundqvist
Katarina
K
Kacprzyk
Lukasz
L
Chalupka
Anna
A
Olsson
Anna-Karin
AK
Mörgelin
Matthias
M
Jahnen-Dechent
Willi
W
Malmsten
Martin
M
Schmidtchen
Artur
A
D000818:Animals; D001665:Binding Sites; D002175:Candida / Q000276:immunology; D002177:Candidiasis / Q000276:immunology*; D002473:Cell Wall; D004875:Ergosterol / Q000378:metabolism; D007113:Immunity, Innate; D051379:Mice; D011485:Protein Binding; D011506:Proteins / Q000276:immunology* / Q000378:metabolism; D013379:Substrate Specificity; D000099053:Histidine-Rich Glycoprotein
D011506:Proteins; D000099053:Histidine-Rich Glycoprotein; D004875:Ergosterol
Ann N Y Acad Sci. 2007 Aug;1109:473-83
17785336
Biochim Biophys Acta. 2007 Nov;1768(11):2667-80
17655823
J Mol Biol. 1970 Jan 14;47(1):69-85
5413343
Biochemistry. 1996 Feb 13;35(6):1925-34
8639676
Nat Rev Immunol. 2003 Sep;3(9):710-20
12949495
Thromb Res. 1985 Dec 1;40(5):653-61
2935971
J Biol Chem. 1999 Jul 2;274(27):18872-9
10383383
FEBS J. 2006 Jun;273(11):2399-406
16704414
Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16879-84
15550543
J Thromb Haemost. 2005 May;3(5):865-72
15869579
Infect Immun. 1993 Jul;61(7):2978-84
8514403
Antimicrob Agents Chemother. 2006 Oct;50(10):3305-11
17005809
J Clin Invest. 2003 Jun;111(11):1643-5
12782665
Cancer Res. 2004 Jan 15;64(2):599-605
14744774
FEBS J. 2007 Jan;274(2):377-89
17229145
Anal Biochem. 1976 May 7;72:248-54
942051
Lipids. 2004 Nov;39(11):1101-13
15726825
J Biol Chem. 1998 Mar 6;273(10):5493-9
9488672
Clin Biochem. 1991 Jun;24(3):241-7
1651820
J Clin Invest. 1986 Apr;77(4):1305-11
3958188
Acta Derm Venereol. 2000 May;80(3):179-84
10954207
Infect Immun. 1997 Jul;65(7):2898-903
9199465
J Leukoc Biol. 2004 Jan;75(1):39-48
12960280
Hoppe Seylers Z Physiol Chem. 1972 Jul;353(7):1133-40
4116337
Ann Acad Med Singap. 1997 Sep;26(5):694-700
9494681
Blood. 1983 Nov;62(5):1016-21
6414553
J Dent Res. 1993 Feb;72(2):517-23
8423249
J Immunol. 2001 Jul 15;167(2):623-7
11441062
Infect Immun. 1984 Jun;44(3):695-701
6724693
J Biol Chem. 2007 Jan 26;282(4):2520-8
17132627
J Invest Dermatol. 1996 Feb;106(2):335-41
8601737
J Biol Chem. 1998 Dec 11;273(50):33115-8
9837875
Curr Opin Hematol. 2002 Jan;9(1):18-22
11753073
Biochim Biophys Acta. 1983 Jan 12;742(1):109-15
6218829
Curr Top Microbiol Immunol. 2006;306:27-66
16909917
Cancer Res. 2004 Aug 15;64(16):5812-7
15313924
Curr Opin Immunol. 1998 Feb;10(1):45-9
9523110
J Immunol Methods. 1991 Mar 21;137(2):167-73
1901580
Nat Rev Microbiol. 2005 Mar;3(3):238-50
15703760
Growth Factors. 2007 Feb;25(1):60-70
17454151
Biochem Soc Symp. 2003;(70):179-99
14587292
Immunol Cell Biol. 2005 Apr;83(2):106-18
15748207
Blood. 2000 Oct 15;96(8):2664-72
11023496
J Endotoxin Res. 2007;13(6):317-38
18182460
Cell Mol Life Sci. 2005 Nov;62(22):2588-98
16261252
Semin Respir Infect. 2001 Mar;16(1):4-10
11309707
Biochemistry. 1994 May 31;33(21):6642-50
8204601
Yeast. 2005 Jul 15;22(9):705-14
16034806
Biochem J. 2004 May 1;379(Pt 3):665-72
14733612
Nat Rev Microbiol. 2008 Jan;6(1):67-78
18079743
Hoppe Seylers Z Physiol Chem. 1972 Jul;353(7):1125-32
4116336
Life Sci. 2002 Jul 5;71(7):747-50
12074933
Biophys J. 2006 Mar 1;90(5):1639-49
16326903
Nature. 2002 Jan 24;415(6870):389-95
11807545
EMBO J. 2006 Nov 29;25(23):5569-78
17093496
Biochim Biophys Acta. 2007 Mar;1768(3):715-27
17207456
Mol Immunol. 2006 Jan;43(1-2):86-96
16023210
J Immunol. 2002 Nov 1;169(9):4745-51
12391183
J Biol Chem. 2005 Oct 14;280(41):34832-9
16091369