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

doi:10.1128/IAI.69.8.5046-5055.2001

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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 immunocompetentmurine models of systemic candidiasis. The pathogenesis of infectionwas evaluated morphologically and by culture of target organs,while the kinetics of induction of cytokine mRNAs and correspondingproteins were determined in kidneys by real-time reverse transcription-PCRand cytokine-specific murine enzyme-linked immunosorbent assays,respectively. Systemic infection with C. glabrata resulted ina chronic, nonfatal infection with recovery of organisms fromkidneys, while intravenous inoculation with C. albicans resultedin rapid mortality with logarithmic growth of organisms in kidneysand recovery of C. albicans from the spleen, liver, and lungs.Survival of C. glabrata-infected mice was associated with rapidinduction of mRNAs and corresponding immunoreactive proteins forthe proinflammatory cytokines tumor necrosis factor alpha (TNF- $alpha$ ),interleukin-12 (IL-12), and gamma interferon (IFN- $gamma$ ) and the lackof induction of protein for the anti-inflammatory cytokine IL-10.In contrast, mortality in C. albicans-infected mice was associatedwith induction of mRNA and corresponding protein for IL-10 butdelayed (i.e., TNF- $alpha$ ) or absent (i.e., IL-12 and IFN- $gamma$ ) inductionof immunoreactive proinflammatory cytokines. Mice were subsequentlytreated with cytokine-specific neutralizing monoclonal antibodies(MAbs) to TNF- $alpha$ , IL-12, or IFN- $gamma$ , and the effect on growth ofC. glabrata in kidneys was assessed. Neutralization of endogenousTNF- $alpha$ resulted in a significant increase in C. glabrata organismscompared to similarly infected mice administered an isotype-matchedcontrol MAb, while neutralization of endogenous IL-12 or IFN- $gamma$ had no significant effect on C. glabrata replication. These resultsdemonstrate that in response to intravenous inoculation of C.glabrata, immunocompetent mice develop chronic nonfatal renalinfections which are associated with rapid induction of the proinflammatorycytokines TNF- $alpha$ , IL-12, and IFN- $gamma$ . Furthermore, TNF- $alpha$ plays akey role in host defense against systemic candidiasis caused byeither C. glabrata or C. albicans, as the absence of endogenousTNF- $alpha$ activity was associated with enhanced tissue burden in bothinfectionmodels.

^* 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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