Access Type

Open Access Dissertation

Date of Award

1-1-2010

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Immunology and Microbiology

First Advisor

MAIRI C. NOVERR

Abstract

Candida albicans, an opportunistic fungal pathogen, poses a significant clinical threat to immunocompromised patients. Diseases associated with this fungus ranges from superficial mucosal infection to life-threatening systemic candidiasis. The mechanisms by which Candida persists at mucosal surfaces in the face of an adaptive response are unclear. Candida produces immunomodulatory oxylipins that cross-react functionally with host eicosanoids, which are considered to play important role in regulating innate and adaptive immune responses. Our objective was to characterize the role of prostaglandins produced by the host and this fungus during host pathogen interactions, both in vitro with dendritic cells (DCs) and macrophages, and in vivo during pathogenesis. At early time point, there was upregulation of Th2 cytokines IL-4, IL-10, and IL-13 by both plasmacytoid and myeloid DCs in the presence of hyphae and PGE2. At later time points, fungal or host PGE2 treatment resulted in decreased Th1 cytokine production (IL-12 and IL-6) and slightly increased Th2 cytokine production (IL-4). DC vaccination experiments demonstrated that yeast pulsed DCs imparted protection, which was abrogated with exposure to host or fungal PGE2. Non-protective responses were associated with Th2 cytokine production, and at later stages, exacerbated Th17 responses accompanied by uncontrolled fungal growth. Ours is the first study to report presence of Th17 cytokines in the mice kidneys during systemic candidiasis and its associated lack of protection. We also demonstrated that during the interaction of C. albicans with the macrophages, PGE2 and PGEx decreased phagocytosis and increased intracellular survival. We also investigated the effects of eicosanoid inhibitors during mucosal and systemic infection models. During experimental C. albicans vaginitis, treatment with inhibitors locally resulted in decreased fungal burden and PGE2 levels. Similar results were observed during systemic infection, which correlated with restoration of Th1 cytokines. These studies suggested that balanced manipulation with eicosanoid production can work without suppressing inflammatory response and inhibit fungal growth at same time. This could provide newer avenues for developing novel pharmacological intervention strategies to treat C. albicans infections.

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