Candida albicans Sap6 dysregulates host epithelial protease-antiprotease expression

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Candida albicans is an oral commensal yeast that can cause mucosal (oral or OPC) and systemic (invasive) infections. Candida mucosal infections are emerging as major public health threat in the US due to higher treatment costs and increased mortality rates particularly among the immunocompromised and critically ill. Thus, there is an urgent need for improved prevention and treatment of mucosal candidiasis. C. albicans hyphal colonize or invade oral epithelial cells that are the first line of physical and immunological defense. C. albicans produces secreted aspartyl proteases (Sap4-6) that counter epithelial immune responses through their proteolytic activity. OECs treated with recombinant Sap6 protease resulted in increased epithelial permeability, increased IL-8, IL-1β release, increased epithelial migration and altered levels of host proteases (kallikreins, matrix metalloprotease and ADAMs). However, we do not know the mechanism by which C. albicans hyphae and Sap6 change host proteases in OECs or which proteases are required for increased fungal invasion, inflammation or changes in OEC migration. Therefore, the Specific Aims of this proposal will 1) Determine how C. albicans Sap6 modifies OEC Kallikrein activity and barrier function, and 2) Examine the role of MMP/ADAM levels on migration of OECs infected with C. albicans or Sap6. The expected outcomes of this work will establish host Kallikreins and matrix metalloproteases as important factors for C. albicans - epithelial interactions and define their role in modulating host inflammatory responses to Sap6 in OECs. Our long-term goal is to understand how C. albicans exploits host proteases/antiproteases to induce acute or chronic immune responses. This will provide much needed ground work to identify host proteases as new therapeutic targets for treating acute and chronic inflammation caused by oral microbes.