Susceptibility of germfree phagocyte oxidase- and nitric oxide synthase 2-deficient mice, defective in the production of reactive metabolites of both oxygen and nitrogen, to mucosal and systemic candidiasis of endogenous origin.
Mice deficient for phagocyte oxidase (Phox) and nitric oxide synthase 2 (NOS2) (gp91phox-/-/NOS2-/-), defective in the production of both reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), were used to investigate the role of phagocytic cells during mucosal and systemic candidiasis of endogenous origin. The alimentary tracts of germfree mice were colonized with Candida albicans wild type or each of two hyphal signaling-defective mutants (efg1/efg1 and efg1/efg1 cph1/cph1). All Candida-colonized gp91phox-/-/NOS2-/- mice were moribund within 12 to 15 days after oral inoculation. C. albicans wild-type and mutant strains colonized the alimentary tracts equally well and were able to translocate, most likely via Peyer's patches and mesenteric lymph nodes, to the internal organs and trigger the formation of abscesses; however, the wild-type and mutant strains did not survive in the abscessed murine tissues. Surprisingly, there was no significant difference in the ability of peritoneal exudate cells from gp91phox-/-/NOS2-/-, NOS2-/-, gp91phox-/-, or immunocompetent C57BL/6 mice to kill C. albicans in vitro. This suggests that anti-Candida factors other than ROI and RNI can control the growth of C. albicans and that gp91phox-/-/NOS2-/- mice die due to the inability of the host to control its inflammatory response to Candida. Correspondingly, reverse transcription-PCR analysis showed increased expression of the cytokines gamma interferon, tumor necrosis factor alpha, and the chemokines MIP-2 and KC at the site of infection, while interleukin-15 expression remained relatively unchanged between germfree and infected tissues. These studies indicate that defects in ROI and RNI enabled C. albicans to translocate and disseminate to the internal organs, resulting in an uncontrolled immune response, severe pathology, and death; however, ROI and RNI were not required for the killing of phagocytized C. albicans, indicating that other anti-Candida factors either compensate or are sufficient for the killing of phagocytized Candida.
Balish
Edward
E
Division of Mycology, Department of Microbiology and Immunology, BSB201, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29403, USA. balish@musc.edu
Warner
Thomas F
TF
Nicholas
Peter J
PJ
Paulling
Emily E
EE
Westwater
Caroline
C
Schofield
David A
DA
D000284:Administration, Oral; D000818:Animals; D002176:Candida albicans / Q000235:genetics / Q000472:pathogenicity*; D002177:Candidiasis / Q000276:immunology* / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism; D004198:Disease Susceptibility; D017353:Gene Deletion; D005856:Germ-Free Life; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000382:microbiology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010586:Phagocytes / Q000276:immunology*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D016207:Cytokines; D008562:Membrane Glycoproteins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
J Infect Dis. 2000 Oct;182(4):1276-9
10979934
J Med Vet Mycol. 1992;30 Suppl 1:179-87
1474442
Clin Microbiol Infect. 2000 May;6(5):251-8
11168121
Int J Med Microbiol. 2001 Mar;290(8):659-68
11310444
Med Mycol. 2001 Jun;39(3):261-8
11446529
Microbiology. 2001 Sep;147(Pt 9):2585-97
11535799
Infect Immun. 2001 Oct;69(10):5991-6
11553535
J Infect Dis. 2002 Feb 15;185(4):521-30
11865405
J Clin Microbiol. 2002 Apr;40(4):1298-302
11923348
J Infect Dis. 2002 Jun 15;185(12):1833-7
12085336
Curr Opin Microbiol. 2002 Aug;5(4):379-85
12160856
J Immunol. 2002 Aug 15;169(4):2093-101
12165537
Science. 2002 Dec 13;298(5601):2195-9
12434011
J Infect Dis. 2003 Aug 15;188(4):591-9
12898449
Clin Microbiol Rev. 2003 Oct;16(4):637-46
14557290
J Clin Microbiol. 2004 Apr;42(4):1519-27
15070998
J Infect Dis. 2004 Oct 1;190(7):1327-34
15346345
J Clin Invest. 1969 Aug;48(8):1478-88
5796360
Infect Immun. 1990 Apr;58(4):1093-100
2180820
Pathol Res Pract. 1990 Aug;186(4):527-34
2247381
J Infect Dis. 1993 Apr;167(4):912-9
8383723
J Infect Dis. 1994 Jul;170(1):180-8
8014495
J Infect Dis. 1995 Jul;172(1):192-8
7541062
Infect Immun. 1996 Aug;64(8):3127-33
8757843
Gastroenterology. 1997 Mar;112(3):1022-7
9041266
Annu Rev Immunol. 1997;15:351-69
9143692
Microbiol Mol Biol Rev. 1997 Jun;61(2):170-92
9184009
Cell. 1997 Sep 5;90(5):939-49
9298905
Diagn Microbiol Infect Dis. 1998 May;31(1):289-96
9597389
J Gastroenterol. 1998 Dec;33(6):792-803
9853550
J Clin Invest. 1998 Dec 15;102(12):2146-55
9854050
Immunity. 1999 Jan;10(1):29-38
10023768
Infect Immun. 1999 Apr;67(4):1828-36
10085024
Clin Exp Immunol. 1999 Mar;115(3):491-7
10193423
Infect Immun. 1999 Jul;67(7):3649-52
10377153
Mol Cell Biol. 2000 Dec;20(23):8696-708
11073971