Role of host iron in C. albicans oral commensal carriage and oropharyngeal candidiasis

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Candida albicans exists as commensal yeast in healthy people while it can cause mucosal and systemic fungal infections in immunocompromised individuals and diabetics. C. albicans has the ability to sense environmental iron as a signal with the help of its signaling pathways, such as Mitogen Activated Protein Kinase (MAPK) Cek1, to modulate gene expression in response to extrinsic iron levels. Recent evidence has shed light on the role of different iron levels between free iron rich gut and free iron deplete blood, allowing C. albicans to choose between a commensal or virulent lifestyle in these respective niches. While it is not known if variation in iron within the oral cavity might also influence virulence during oral candidiasis, our preliminary data shows that iron chelation in murine oral candidiasis causes significantly enhanced virulence; and that higher salivary iron levels in humans correlate with a higher frequency of oral C. albicans carriage. The main goal of this project is to understand the role of host iron levels in modulating the oral growth of C. albicans. We will use our murine oral candidiasis model and mice will be repleted or depleted in systemic iron levels with iron supplementation (with iron dextran) and iron chelation (with iron chelator Deferasirox), respectively. Our overall hypothesis is that host iron levels either promote oral commensal carriage (under relative high free iron conditions) or virulence (under relative low free iron conditions) by influencing C. albicans gene expression and host macrophage function. We will test our hypothesis using two specific aims: 1) Determine whether host iron modulates C. albicans carriage and infection levels in the oral cavity, and identify iron-dependent changes in in vivo fungal gene expression and 2) Evaluate the effect of changes in host and C. albicans iron levels on phagocytosis by macrophages and subsequent intracellular survival of C. albicans. This work will provide insights into the potential use of salivary iron levels as a marker for susceptibility to enhanced oral Candidal carriage and oropharyngeal candidiasis.