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.

概括强调对白色念珠菌引起的口咽念珠菌病（OPC；鹅口疮）易感性的因素不同人群的情况尚不十分清楚。在患有特定单基因疾病的个体中，OPC 易感性取决于粘膜免疫防御和/或上皮屏障功能的缺陷。在癌症中在接受化疗的患者中，OPC 被归因于白细胞减少的严重程度，但也有对其他诱发因素在这种情况下所起的作用的了解不完全。小鼠模型已显示口腔细菌通过促进白色念珠菌的生长而导致化疗相关 OPC 的严重程度丝状形成和上皮损伤。然而，需要从人类研究中获取有关因素的证据使接受化疗的患者易患 OPC，包括了解 OPC 所起的作用细菌，以及宿主抗真菌防御的描述，当化疗破坏该防御时，会导致 OPC。评估个体的机会促进了化疗中 OPC 敏感性的研究 OPC 进展之前和进展期间。该提案基于最近试点中获得的初步数据使用这种独特的临床模型进行研究，在该模型中我们建立了宿主的临床特征和口腔化疗前评估的微生物组组成构成 OPC 的危险因素。我们还评估了化疗诱发 OPC 的方式，发现唾液腺分泌不足和中性粒细胞减少症同样重要贡献者。这些结果表明化疗期间 OPC 的病因是多因素的。此举的目标该提案的目的是确定化疗接受者对 OPC 易感性的因素。通过临床和体外机制研究，该提案将检验特定临床、免疫学的假设微生物特征决定了化疗期间对 OPC 的敏感性。为了获得更好的理解为了研究化疗期间 OPC 的病理生理学，提出了三个具体目标。在目标 1 中，我们将开发基于基线医学和口腔特征以及口腔微生物组进行预测的机器学习模型化疗接受者中 OPC 的发生率。我们期望创建一个工具来识别、预输注、个人易受 OPC 影响。在目标 2 中，我们将纵向确定化疗、唾液与 OPC 发病相关的抗真菌防御、粘膜完整性和口腔微生物组。我们预计这些研究将揭示宿主和微生物组因素，当受化疗影响时，这些因素容易诱发到OPC。在目标 3 中，我们将通过体外研究评估与 OPC 相关的细菌种类的潜力病变以改变白色念珠菌的毒力。这些研究将确定白色念珠菌的关键细菌伙伴并阐明王国间相互作用可能导致化疗相关 OPC 的方式。总之，这些研究将为化疗期间 OPC 的病因学提供临床相关证据我们期望这将有助于指导预防和治疗干预措施的制定。