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Infection and Immunity, August 2001, p. 5046-5055, Vol. 69, No. 8
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.8.5046-5055.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Comparison of Pathogenesis and Host Immune Responses to Candida glabrata and Candida albicans in Systemically Infected Immunocompetent Mice

Joan Brieland,1,* David Essig,1 Craig Jackson,1 Doyle Frank,2 David Loebenberg,1 Fred Menzel,1 Brian Arnold,1 Beth DiDomenico,1 and Roberta Hare1

Departments of Chemotherapy1 and Drug Safety,2 Schering Plough Research Institute, Kenilworth, New Jersey

Received 12 January 2001/Returned for modification 8 March 2001/Accepted 5 May 2001

Cytokine-mediated host defense against Candida glabrata infection was compared to that against C. albicans, using immunocompetent murine models of systemic candidiasis. The pathogenesis of infection was evaluated morphologically and by culture of target organs, while the kinetics of induction of cytokine mRNAs and corresponding proteins were determined in kidneys by real-time reverse transcription-PCR and cytokine-specific murine enzyme-linked immunosorbent assays, respectively. Systemic infection with C. glabrata resulted in a chronic, nonfatal infection with recovery of organisms from kidneys, while intravenous inoculation with C. albicans resulted in rapid mortality with logarithmic growth of organisms in kidneys and recovery of C. albicans from the spleen, liver, and lungs. Survival of C. glabrata-infected mice was associated with rapid induction of mRNAs and corresponding immunoreactive proteins for the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha ), interleukin-12 (IL-12), and gamma interferon (IFN-gamma ) and the lack of induction of protein for the anti-inflammatory cytokine IL-10. In contrast, mortality in C. albicans-infected mice was associated with induction of mRNA and corresponding protein for IL-10 but delayed (i.e., TNF-alpha ) or absent (i.e., IL-12 and IFN-gamma ) induction of immunoreactive proinflammatory cytokines. Mice were subsequently treated with cytokine-specific neutralizing monoclonal antibodies (MAbs) to TNF-alpha , IL-12, or IFN-gamma , and the effect on growth of C. glabrata in kidneys was assessed. Neutralization of endogenous TNF-alpha resulted in a significant increase in C. glabrata organisms compared to similarly infected mice administered an isotype-matched control MAb, while neutralization of endogenous IL-12 or IFN-gamma had no significant effect on C. glabrata replication. These results demonstrate that in response to intravenous inoculation of C. glabrata, immunocompetent mice develop chronic nonfatal renal infections which are associated with rapid induction of the proinflammatory cytokines TNF-alpha , IL-12, and IFN-gamma . Furthermore, TNF-alpha plays a key role in host defense against systemic candidiasis caused by either C. glabrata or C. albicans, as the absence of endogenous TNF-alpha activity was associated with enhanced tissue burden in both infection models.

* Corresponding author. Mailing address: Schering Plough Research Institute, 2015 Galloping Hill Road, K15-B432 4800, Kenilworth, NJ 07033. Phone: (908) 740-3147. Fax: (908) 740-3918. E-mail: joan.brieland{at}spcorp.com.

Infection and Immunity, August 2001, p. 5046-5055, Vol. 69, No. 8
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.8.5046-5055.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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