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Mucosal Immune Defenses to the Fungal Pathogen Candida albicans

Tomalka, Jeffrey Alan

Abstract Details

2013, Doctor of Philosophy, Case Western Reserve University, Pathology.
Fungal pathogens represent one of the greatest emerging threats to human health. In spite of this, limited research has been conducted on the mechanisms utilized to clear fungi. We first discovered that IL-1ß is critical for mounting an effective immune response to Candida albicans. It was recently discovered that proteolytic cleavage of IL-1ß, a required step in its release and activity, can be mediated by intracellular protein complexes termed “inflammasomes” which consist, in part, of members of the NLR family of proteins. Given the critical role for IL-1ß in our model, we next investigated the NLR(s) responsible for Candida induced IL-1ß. We found that NLRP3 was indispensable for production of IL-1ß from macrophages. Nlrp3-/- mice had elevated oral fungal loads early, with sustained increases in disseminated infection through the course of infection. Despite the absolute requirement for NLRP3 in IL-1ß release from macrophages, levels of circulating IL-1ß were still detectable in the absence of both NLRP3 and ASC. This led to the hypothesis that an additional CARD containing NLR was functioning to induce IL-1ß release following live Candida infection. Nlrc4-/- macrophages exhibited no defect in IL-1ß release however serum from infected mice did exhibit a substantial reduction in IL-1ß. Mice deficient in NLRC4 were susceptible to sustained mucosal infection and early bloodstream dissemination. Bone marrow chimeric mice revealed that WT bone marrow transplant was incapable of ameliorating disease in Nlrc4-/- hosts and Nlrp3-/- bone marrow induced susceptibility to infection in WT mice, demonstrating these two NLRs exert their function in different cells. Absence of either NLR was found to result in decreased neutrophil infiltration into infected tongues and decreased inflammatory gene expression in buccal tissue, including a substantial defect in ß-defensin expression. The profound defect in ß-defensins led to the investigation of the capacity for murine ß-defensin 1 to protect from oral Candida infection. Mice deficient in this protein exhibited increased mucosal and disseminated fungal loads at early timepoints. Concurrent with this early susceptibility was decreased neutrophils and inflammatory gene expression in infected mucosal tissue. These data demonstrate the critical role of IL-1ß during protective mucosal immune responses to Candida.
Amy Hise, M.D., MPH (Advisor)
George Dubyak, Ph.D. (Committee Chair)
Alan Levine, Ph.D. (Committee Member)
Eric Pearlman, Ph.D. (Committee Member)
Derek Abbott, M.D., Ph.D. (Committee Member)
Clive Hamlin, Ph.D. (Committee Member)
201 p.

Recommended Citations

Citations

  • Tomalka, J. A. (2013). Mucosal Immune Defenses to the Fungal Pathogen Candida albicans [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1370885222

    APA Style (7th edition)

  • Tomalka, Jeffrey. Mucosal Immune Defenses to the Fungal Pathogen Candida albicans. 2013. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1370885222.

    MLA Style (8th edition)

  • Tomalka, Jeffrey. "Mucosal Immune Defenses to the Fungal Pathogen Candida albicans." Doctoral dissertation, Case Western Reserve University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1370885222

    Chicago Manual of Style (17th edition)