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Infection and Immunity, March 2005, p. 1313-1320, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1313-1320.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Edward Balish,1* Thomas F. Warner,2 Peter J. Nicholas,1 Emily E. Paulling,1 Caroline Westwater,3 and David A. Schofield1

Department of Microbiology and Immunology,1 Department of Stomatology, Medical University of South Carolina, Charleston, South Carolina,3 Department of Surgical Pathology, University of Wisconsin Medical School, Madison, Wisconsin2

Received 30 September 2004/ Returned for modification 1 November 2004/ Accepted 19 November 2004

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.

* Corresponding author. Mailing address: Division of Mycology, Department of Microbiology and Immunology, BSB201, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29403. Phone: (843) 792-6317. Fax: (843) 792-2464. E-mail: balish{at}musc.edu.

Editor: T. R. Kozel

Infection and Immunity, March 2005, p. 1313-1320, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1313-1320.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Balish, E. (2009). A URA3 null mutant of Candida albicans (CAI-4) causes oro-oesophageal and gastric candidiasis and is lethal for gnotobiotic, transgenic mice (Tg{epsilon}26) that are deficient in both natural killer and T cells. J Med Microbiol 58: 290-295 [Abstract] [Full Text]  
  • Wellington, M., Dolan, K., Krysan, D. J. (2009). Live Candida albicans Suppresses Production of Reactive Oxygen Species in Phagocytes. Infect. Immun. 77: 405-413 [Abstract] [Full Text]  
  • Westwater, C., Balish, E., Warner, T. F., Nicholas, P. J., Paulling, E. E., Schofield, D. A. (2007). Susceptibility of gnotobiotic transgenic mice (Tg{epsilon}26) with combined deficiencies in natural killer cells and T cells to wild-type and hyphal signalling-defective mutants of Candida albicans. J Med Microbiol 56: 1138-1144 [Abstract] [Full Text]  
  • Hromatka, B. S., Noble, S. M., Johnson, A. D. (2005). Transcriptional Response of Candida albicans to Nitric Oxide and the Role of the YHB1 Gene in Nitrosative Stress and Virulence. Mol. Biol. Cell 16: 4814-4826 [Abstract] [Full Text]  


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