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

• 批准号: 10504413
• 负责人: Patricia Diaz
• 金额: $ 79.78万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 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/10504413
• 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; Data; Defect; Dental Plaque Index; Development; Dose; Epithelial; Etiology; Filament; Functional disorder; Future; Gene Expression; Genetic Transcription; Goals; Habits; Human; Immune; Immunologics; In Vitro; Incidence; Individual; Infection; Infusion procedures; Intake; 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; Role; Salivary; Sampling; Severities; Smoking; Streptococcus; Systemic infection; Testing; Therapeutic Intervention; Time; Virulence; Virulence Factors; Xerostomia; bacteriome; base; cancer therapy; chemotherapy; clinical application; clinically relevant; comorbidity; design; experimental study; future implementation; host microbiome; 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; tool

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 强调对念珠菌念珠菌引起的口咽念珠菌病（OPC;鹅口疮）的敏感性的因素 在不同的人群中，人们的理解不高。在患有特定单基因疾病的个体中 敏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 接受化学疗法的患者OPC归因于白细胞减少的严重程度，但是有 在这种情况下，对其他诱发因素所起的作用不完全理解。鼠标模型已显示 该口腔细菌通过促进白色念珠菌有助于化学疗法相关的OPC的严重程度 细丝和上皮损害。但是，有必要从人类研究中获得有关因素的证据 这种易感患者接受化学疗法的患者，包括了解 细菌，以及宿主抗真菌防御剂的描述，当化学疗法妥协时， OPC。评估个体的机会促进了化学疗法中OPC易感性的研究 OPC进展之前和期间。该提案基于最近的试点中获得的初步数据 使用这种独特的临床模型的研究，我们确定了宿主的临床特征和口腔 化学疗法之前评估的微生物组组成构成OPC的危险因素。我们还评估了 化学疗法容易患OPC的方式，发现缺失和中性粒细胞减少症很重要 贡献者。这些结果表明化学疗法期间OPC的多因素病因。目标的目标 建议是确定在化学疗法接受者中强调OPC敏感性的因素。通过 临床和体外机理研究，该提案将检验以下假设。 微生物特征决定了化学疗法期间对OPC的敏感性。获得更好的理解 在化学疗法期间，OPC的病理生理学提出了三个特定目标。在目标1中，我们将发展 基于基线医学和口服特征的机器学习模型以及预测的口服微生物组 化学疗法接受者的OPC发病率。我们预计会创建一种工具来识别，预灌注，个人 容易受到OPC的影响。在AIM 2中，我们将纵向确定化学疗法，唾液之间的相互作用 抗真菌防御，粘膜完整性和与OPC发病率相关的口服微生物组。我们 预计这些研究将揭示宿主和微生物组因子，而当受到化学疗法影响时 致OPC。在AIM 3中，我们将通过体外研究评估与OPC相关的细菌物种的潜力 改变白色念珠菌的毒力的病变。这些研究将确定白色念珠菌的关键细菌伴侣 并阐明了昆神之间的相互作用可能有助于化学疗法相关的OPC的方式。 总之，这些研究将提供有关化学疗法期间OPC病因的临床证据 我们希望这将有助于指导预防和治疗性干预措施的发展。