Pilot--IL-12 inhibition of Candida albicans

Case Western Reserve University, Cleveland OH

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Abstract

Candida albicans (CA) is a major opportunistic fungal pathogen, most importantly, it causes mucocutaneous as w4ell as systemic candidiasis resulting in high mortality in immuno-compromised hosts. Upon damage to the epithelium or epidermis by candidal hyphae, and the activation of chemoattractive mediator (i.e. chemokines and complement), newly arriving monocytes (MO) and tissue macrophages (Mph) contribute either to the defense against or propagation of these infection. However, their functions in pathogenesis of candidiasis in humans have not been fully explored. Our preliminary data reveal that CA, unlike the less virulent C. krusei (CK), inhibits IL-12 production by MO. In addition, heat killed (HK) CA does not inhibit but induces IL-122 production, suggesting that a process(s) associated with viable candidal cells is required to inhibit production of this cytokine and counteracts an innate mechanism for IL- 12 induction which will promote adaptive immunity to CA and induction of IFNgamma inhibition. Additionally, supernatant obtained from germinating CA hyphae possesses factors that inhibit IL-12 production by MO. We hypothesize that hyphae play a critical role in inhibition of IL- 12 production by human MO. Isogenic C. albicans strain pairs, differing only in the ability to germinate, will be employed to determine if this hypothesis is valid. Because germinative CA express a ligand for complement receptor 3(CR3) on MO and we have previously shown that iC3b (which binds CR3) triggers inhibition of IL-12 in MO, we further hypothesize that inhibition of IL-12 by the binding of CA to CR3 on MO. Experiments will be performed with blocking antibodies to CR3, soluble iC3b to block CA ligand binding to CR3 and a human MO cell line that is deficient in CR3. The results of our proposed experiments will reveal if CA hyphae are involved in altering the host immune response and whether the mechanism involve CA interacting with CR3 on MO. Such an understanding may stimulate the development of novel therapies for treating Candidiasis based upon surface ligands expressed during germination.