Salivary Zinc modifies Histatin 5 activity towards C. albicans survivor cells and commensalism

Candida albicans is an opportunistic fungus and the causative agent of oropharyngeal candidiasis (OPC) that develops in a wide spectrum of immunocompromised people. However, in healthy populations, C. albicans is a commensal organism that is part of the oral microbiome. Salivary Histatin 5 (Hst 5) is a highly abundant salivary protein that is well characterized for its fungicidal activity. Hst 5 contains six histidine residues that comprise two zinc-binding motifs. Zinc (Zn) is the most abundant salivary metal, and Zn binding with Hst 5 causes oligomerization of Hst 5 that alters it fungicidal activity. We found that treated C. albicans cells exposed to low doses of Hst 5/Zn2+ recover as phenotypically different “survivor cells” that have altered cell wall composition, increased adhesion and reduced invasion of oral epithelial cells (OECs) along with dampened OEC inflammatory responses. Our hypothesis is that the major role of salivary Hst 5 when bound with zinc in vivo is to promote commensalism of oral C. albicans thus maintaining this organism as member of the healthy oral microbiome. We will test our hypothesis with following Specific Aims: 1. Determine whether cell wall changes in Hst5-Zn induced survivor cells modify susceptibility to cell wall targeting antifungal drugs or alter binding with their microbial mucosal binding partners. Aim 2. Determine how survivor cells modulate OECs inflammatory responses and alter Candida colonization along with mucosal binding partners in vitro. Aim 3. Test commensalism of survivor cells in vivo using a murine model of oral candidiasis by altering ambient oral zinc levels. Our goal is to fully understand the how salivary Hst 5-Zn complexes might promote commensalism and maintain a healthy homeostasis with mucosal oral binding partners, so that future clinical studies might be directed to therapeutic oral rinses that alter zinc levels to improve the function of Hst 5.