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

总结 白念珠菌引起的口咽念珠菌病（OPC;鹅口疮）易感性的因素 在不同的人群中并没有得到很好的理解。在患有特定单基因疾病的个体中，OPC 粘膜免疫防御和/或上皮屏障功能的缺陷决定了易感性。在癌症中 在接受化疗的患者中，OPC已被归因于白细胞减少症的严重程度，但 对其他诱发因素在这种情况下所起的作用的不完全理解。小鼠模型显示， 口腔细菌通过促进C.白色 以及上皮损伤。然而，有必要从人类研究中获得有关因素的证据， 使接受化疗的患者易患OPC，包括了解 细菌，并描绘了宿主抗真菌防御，当化疗导致妥协， OPC。化疗中OPC敏感性的研究是通过评估个体的机会来促进的。 在OPC进展之前和期间。这一提议是根据最近一次试点获得的初步数据提出的 使用这种独特临床模型进行研究，其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的风险因素。我们还评估了 化疗倾向于OPC的方式，发现唾液减少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的多因素病因。这个目标 该研究的目的是确定化疗受者对OPC易感性的因素。通过 临床和体外机制研究，该提案将测试特定的临床，免疫学 和微生物特征决定了化疗期间对OPC的敏感性。更好地了解 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的机器学习模型， 化疗受者的OPC发生率。我们期望创造一种工具， 对OPC敏感。在目标2中，我们将纵向地确定化疗、唾液腺分泌和免疫抑制之间的相互作用。 抗真菌防御、粘膜完整性和口腔微生物组与OPC发病率相关。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， 在OPC。在目标3中，我们将通过体外研究评估与OPC相关的细菌种属的可能性 病变改变C.白色念珠菌这些研究将确定C.白色 并阐明界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 我们期望这些信息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.