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

摘要 白色念珠菌引起口咽念珠菌病(OPC；鹅口疮)的易感性因素 在不同的人群中，人们还没有很好地理解。在患有特定单基因疾病的个体中，OPC 易感性是由粘膜免疫防御和/或上皮屏障功能缺陷决定的。在癌症中 接受化疗的患者，OPC一直被归因于白细胞减少的严重程度，但有 对其他诱因在这种情况下所起作用的认识不全面。老鼠模型已经显示出 口腔细菌通过促进白色念珠菌促进化疗相关OPC的严重程度 丝状化和上皮损伤。然而，有必要从有关因素的人体研究中获得证据。 使接受化疗的患者易于进入OPC，包括了解 细菌，以及宿主抗真菌防御系统的描绘，当被化疗损害时，这些防御系统会导致 OPC。通过评估个体的机会，促进了对化疗中OPC敏感性的研究 在OPC进展之前和期间。这一建议是基于最近的一次试点中获得的初步数据 使用这种独特的临床模式进行研究，在该模式中我们建立了宿主临床特征和口腔 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 化疗易患OPC的方式，发现肺功能低下和中性粒细胞减少是重要的 贡献者。这些结果表明化疗期间OPC的病因是多因素的。这样做的目的是 建议确定化疗受者对OPC易感性的因素。穿过 临床和体外机制研究，这一建议将检验特定的临床、免疫学假说 微生物特性决定了化疗期间对OPC的易感性。为了更好地了解 针对OPC在化疗过程中的病理生理机制，提出了三个具体的研究目标。在目标1中，我们将制定 基于基线医学和口腔特征和口腔微生物群预测的机器学习模型 化疗受者中OPC的发生率。我们期待着创造一种工具来识别、预先输液、 易受OPC的影响。在目标2中，我们将纵向确定化疗和唾液之间的相互作用 抗真菌防御、粘膜完整性和口腔微生物群与OPC的发生有关。我们 预计这些研究将揭示宿主和微生物组因素，当受到化疗影响时，容易发生 致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。 损伤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。 并阐明王国之间的相互作用可能有助于化疗相关的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发展。

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.