SUMMARY The factors that underline susceptibility to oropharyngeal candidiasis (OPC; thrush) caused by Candida albicans in different populations are not well understood. In individuals with specific monogenic disorders, OPC susceptibility is dictated by defects in mucosal immune defenses and/or epithelial barrier function. In cancer patients undergoing chemotherapy, OPC has been attributed to the severity of leukopenia, but there is incomplete understanding of the role other predisposing factors play in this setting. Mouse models have shown that oral bacteria contribute to the severity of chemotherapy-associated OPC by promoting C. albicans filamentation and epithelial damage. There is a need, however, to obtain evidence from human studies on factors that predispose patients receiving chemotherapy to OPC, including an understanding of the role played by bacteria, and a delineation of the host antifungal defenses that when compromised by chemotherapy lead to OPC. The study of OPC susceptibility in chemotherapy is facilitated by the opportunity to evaluate individuals prior to and during progression of OPC. This proposal is based on preliminary data obtained in a recent pilot study using this unique clinical model in which we established that host clinical characteristics and the oral microbiome composition assessed prior to chemotherapy constitute risk factors for OPC. We also evaluated the manner in which chemotherapy predisposes to OPC, discovering hyposalivation and neutropenia as important contributors. These results suggest a multi-factorial etiology for OPC during chemotherapy. The goal of this proposal is to determine the factors that underline susceptibility to OPC in chemotherapy recipients. Through clinical and in vitro mechanistic studies, this proposal will test the hypothesis that specific clinical, immunological and microbial characteristics dictate susceptibility to OPC during chemotherapy. To gain a better understanding of the pathophysiology of OPC during chemotherapy three specific aims are proposed. In Aim 1 we will develop a machine-learning model based on baseline medical and oral characteristics and the oral microbiome to predict OPC incidence in chemotherapy recipients. We anticipate creating a tool to identify, pre-infusion, individuals susceptible to OPC. In Aim 2, we will identify, longitudinally, the interactions between chemotherapy, salivary antifungal defenses, mucosal integrity and the oral microbiome that are associated with OPC incidence. We expect these studies will reveal the host and microbiome factors that when affected by chemotherapy predispose to OPC. In Aim 3, we will evaluate through in vitro studies the potential for bacterial species associated with OPC lesions to modify the virulence of C. albicans. These studies will identify critical bacterial partners of C. albicans and elucidate the manner in which inter-kingdom interactions may contribute to chemotherapy-associated OPC. Altogether, these studies will provide clinically-relevant evidence on the etiology of OPC during chemotherapy that we expect will contribute to guide the development of preventive and therapeutic interventions.

PROJECT NARRATIVE Twenty to forty percent of cancer patients treated with chemotherapy develop oropharyngeal candidiasis (OPC), also known as thrush. Prevention of OPC during cancer treatment could lead to better compliance and quality of life, reductions in risk of systemic infection and decreased antifungal use. This proposal aims to identify the host and microbiome factors that contribute to OPC susceptibility in chemotherapy recipients and can serve as targets for preventive interventions.