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Host and microbial risk factors of oral thrush in cancer patients receiving chemotherapy

接受化疗的癌症患者鹅口疮的宿主和微生物危险因素

基本信息

批准号：
10677005
负责人：
Patricia Diaz
金额：
$ 77.08万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-04 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677005
关键词：
Adhesions Affect Animal Model Antifungal Agents Area Bacteria Bioinformatics Cancer Center Cancer Patient Candida albicans Characteristics Chemotherapy-Oncologic Procedure Clinical Clinical Research Coculture Techniques Data Defect Dental Plaque Index Development Dose Epithelium Etiology Filament Functional disorder Future Gene Expression Genetic Transcription Goals Habits Human Immune Immunologics In Vitro Incidence Individual Infection Infusion procedures Intake Invaded Knowledge Lactobacillus Lead Lesion Leukopenia Measures Mediating Medical Medical History Mendelian disorder Modeling Mucous Membrane Multi-Drug Resistance Neutropenia Nutritional Observational Study Oral Oral candidiasis Oral mucous membrane structure Pathogenicity Patient Schedules Patients Peripheral Pilot Projects Play Population Porphyromonas Predisposing Factor Predisposition Prevention Prevention strategy Preventive Prevotella Property Quality of life ROC Curve Research Infrastructure Resistant candida Risk Risk Factors Risk Marker Role Salivary Sampling Severities Smoking Streptococcus Systemic infection Testing Therapeutic Intervention Time Virulence Virulence Factors Xerostomia bacteriome cancer therapy chemotherapy clinical application clinically relevant cohort comorbidity design experimental study future implementation in vivo longitudinal analysis machine learning model microbial microbiome microbiome composition mouse model mycobiome neutrophil oral bacteria oral microbiome oral mucositis oropharyngeal thrush patient population predictive modeling preventive intervention prospective response therapy development tool

项目摘要

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.

总结