Oral Epithelial Cells, Candida and PMN Activation

About This Grant

Abstract Oropharyngeal Candidiasis (OPC) is a common fungal infection afflicting populations with immature or weakened immune systems. Like other oral diseases in which commensal microbes become pathogenic, OPC is associated with a dysbiotic state, an alteration in the composition and abundance of the oral health- associated bacteria, contributing to a permissive environment for Candida spp. infection. An aging population, the rise in the use of immune-compromising treatments and the increasing prevalence of drug- resistant Candida strains make it imperative to find alternative treatments for OPC. While microbiome manipulation therapies have been effective in intestinal dysbiotic diseases, none have yet been established for oral microbiome-related diseases. Microbiome directed therapies include reconstitution with probiotic bacterial consortia, that can promote oral mucosal homeostasis. It remains extremely important not only to discover new probiotic organisms but also to unravel their mechanism of action and understand their strain- specific effect. Work in our previous funding cycle showed that C. albicans causes a severe dysbiotic shift in the oral mucosal microbiota with significant reduction in bacterial alpha diversity. We also demonstrated pathogenic synergy of indigenous dysbiotic bacteria with C. albicans and identified cellular and molecular mechanisms of this synergy. Importantly, using two different types of dietary interventions in the murine OPC model we found that the oral bacterial dysbiotic shift is reversible and that diet-induced increased abundance of the commensal species Lactobacillus johnsonii is associated with less severe infection. In the next funding cycle, we propose to demonstrate that L. johnsonii induces changes in the oral bacterial microbiome consistent with mucosal homeostasis and examine mechanisms of this activity (aim 1). We also propose to demonstrate a role for this organism and its associated symbiotic bacteria in limiting the risk of C. albicans infection in immunosuppressed hosts (aim 2). In aim 3 we will dive deeper in the mechanism of protection of the oral mucosal barrier by evaluating the ability of L. johnsonii to inhibit oral epithelial adhesion, invasion and damage by C. albicans; and to inhibit Candida-induced mucosal inflammation and barrier breach. Our innovative studies will explore probiotic bacterial mechanisms that leverage the interactions between resident host bacterial microbiota, oral epithelial cells and opportunistic pathogenic fungi, providing a foundational step towards personalized, microbiome-centered treatments beyond traditional antifungal medications in oropharyngeal candidiasis. This research proposal is significant because it advances the search for alternative microbiome-targeted therapies in oral fungal infections.