Candida albicans heme oxygenase and its product CO contribute to pathogenesis of candidemia and alter systemic chemokine and cytokine expression.
Mammalian heme oxygenases play important roles in immune regulation by producing immunosuppressive CO. The pathogenic yeast Candida albicans encodes a heme oxygenase, Hmx1, that is specifically induced by the host protein hemoglobin, suggesting a role in the pathogenesis of disseminated bloodstream infections. We show that exposing mice to therapeutic levels of CO increases C. albicans virulence, whereas an HMX1 null strain has decreased virulence in murine disseminated candidiasis. Levels of several regulatory cytokines and chemokines are decreased in mice infected with the null strain, and initial lesions in the kidney are more rapidly cleared after polymorphonuclear leukocyte infiltration. Reconstitution of one or both alleles restores virulence to the level of wild type. Growth in vitro and initial organ burdens in infected mice are not decreased and host iron overload does not restore virulence for the null strain, suggesting that early growth in the host is not limited by Hmx1-mediated iron scavenging. In contrast, inhaled CO partially reverses the virulence defect of the null strain and restores several host cytokine responses to wild-type levels. Collectively, these results show that C. albicans Hmx1 expression and CO production limit the host immune response and contribute to the pathogenesis of candidemia.
Navarathna
Dhammika H M L P
DH
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20982-1500, USA.
Roberts
David D
DD
D000818:Animals; D002176:Candida albicans / Q000201:enzymology / Q000472:pathogenicity*; D058387:Candidemia / Q000209:etiology*; D002248:Carbon Monoxide / Q000633:toxicity*; D018925:Chemokines / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D051547:Heme Oxygenase-1 / Q000633:toxicity*; D019190:Iron Overload / Q000503:physiopathology; D007668:Kidney / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D014774:Virulence / Q000187:drug effects
D018925:Chemokines; D016207:Cytokines; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1
Infect Immun. 2007 Apr;75(4):1609-18
17283095
Exp Physiol. 2009 Jun;94(6):720-30
19201785
J Immunol. 2005 Oct 1;175(7):4408-15
16177082
J Appl Physiol. 1960 Mar;15:321-3
13819807
J Immunol. 2008 May 1;180(9):5771-7
18424693
Curr Pharm Des. 2008;14(5):454-64
18289072
FEMS Immunol Med Microbiol. 1999 Dec;26(3-4):299-307
10575142
Infect Immun. 2007 Aug;75(8):4006-11
17517874
Infect Immun. 2001 Aug;69(8):5046-55
11447185
Brain Res. 2002 Nov 1;954(1):51-9
12393232
Med Mycol. 2000 Jun;38(3):213-9
10892989
Infect Immun. 2009 Apr;77(4):1596-605
19188358
Oral Microbiol Immunol. 2006 Aug;21(4):252-5
16842510
J Infect Dis. 2004 Aug 1;190(3):624-31
15243941
Biol Res Nurs. 2007 Apr;8(4):300-4
17456591
Blood. 1969 Oct;34(4):441-51
4980682
Arch Biochem Biophys. 2004 Jun 15;426(2):148-56
15158665
J Exp Med. 2009 Feb 16;206(2):299-311
19204111
Am J Clin Pathol. 1976 Jun;65(6):991-1000
779443
Med Mycol. 2001 Feb;39(1):41-50
11270407
Eukaryot Cell. 2004 Jun;3(3):764-75
15189997
Mycopathologia. 1985 Jan;89(1):59-63
3982493
Biochem J. 1980 Aug 1;189(2):193-208
7458909
Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G695-703
16537973
Curr Opin Microbiol. 1999 Aug;2(4):363-7
10458979
Cell Host Microbe. 2009 Apr 23;5(4):329-40
19380112
Science. 1995 Dec 15;270(5243):1811-5
8525373
PLoS One. 2009 Jul 29;4(7):e6420
19641609
Gene. 1987;57(2-3):267-72
3319781
Nat Med. 2000 Apr;6(4):422-8
10742149
J Med Microbiol. 2007 Sep;56(Pt 9):1167-1173
17761478
J Immunol. 2006 Oct 1;177(7):4749-57
16982915
J Exp Med. 2000 Oct 2;192(7):1015-26
11015442
Methods Enzymol. 1991;194:398-405
1706459
Immunology. 2006 Jan;117(1):38-46
16423039
J Bacteriol. 2000 Dec;182(23):6783-90
11073924
Microbiol Rev. 1978 Mar;42(1):45-66
379572
J Antimicrob Chemother. 2005 Dec;56(6):1156-9
16239285
N Engl J Med. 1989 Nov 23;321(21):1426-32
2682242
Front Biosci. 2008 May 01;13:3334-51
18508436
Mod Pathol. 1994 Jun;7(5):599-604
7524071
Biochemistry. 2006 Dec 12;45(49):14772-80
17144670
Infect Immun. 1992 Nov;60(11):4907-14
1399001
J Bacteriol. 2001 Nov;183(21):6394-403
11591684
Immunology. 2009 Feb;126(2):177-85
19125888
Int Immunol. 1998 Jan;10(1):37-48
9488154
Microbiology (Reading). 2003 Mar;149(Pt 3):579-588
12634327
Mol Gen Genet. 1984;198(2):179-82
6394964
Infect Immun. 2005 Sep;73(9):5482-92
16113264
FEMS Yeast Res. 2009 Oct;9(7):1111-22
19845042
J Med Microbiol. 2006 Mar;55(Pt 3):251-258
16476787
Gene. 2004 Oct 27;341:119-27
15474295
J Biol Chem. 2004 Jan 30;279(5):3426-33
14615478
Circ Res. 2007 Jun 22;100(12):1703-11
17495224
J Cell Mol Med. 2006 Jul-Sep;10(3):672-86
16989727
Am J Physiol Heart Circ Physiol. 2002 Sep;283(3):H861-70
12181112
Expert Opin Biol Ther. 2006 Sep;6(9):891-903
16918256