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.