Oral Epithelial Cells, Candida and PMN Activation

项目总结 口腔黏膜微生物区系是一个以细菌和真菌为主要代表的复杂生态系统。多数 口咽真菌感染是由念珠菌属引起的，被认为是由一种 本土物种的过度生长，主要是白色念珠菌。白色念珠菌是口腔的一种共生定殖者。 人类的粘膜，但也是感染折磨免疫功能受损的宿主的原因。持久化 口咽鹅口疮对大多数抗真菌药物耐药，在药理学上是一个重要的临床问题。 免疫抑制的病人。皮质类固醇诱导的免疫抑制和化疗诱导的免疫抑制是两种 口咽部念珠菌病的主要危险因素。白念珠菌还会导致真菌血症，这是一种严重的 癌症细胞毒性化疗的后果，被认为是由真菌易位通过 粘膜屏障受损。内源细菌种群大小或组成的变化以及 寄主环境可以将真菌共生体转化为病原菌。在我们上一个资金周期中的工作 口腔霉菌群链球菌与白色念珠菌在口腔溃疡发病中的协同作用 念珠菌病。我们确定了协同作用的机制，包括对真菌毒力基因的直接影响 表达和修饰宿主反应。在这个项目中，我们将以我们正在进行的研究为基础 口腔黏膜细菌群与白色念珠菌的相互作用。我们将使用鼠标模型 共生定植或粘膜感染来询问促进口腔细菌微生物群参数 白念珠菌的致病力。在目标1中，我们将描述粘膜相关细菌的非生理性变化。 口咽部念珠菌病的群落，使用我们建立的可的松-和 化疗引起的免疫抑制。然后我们将测试某些内源性细菌 从不良生物状态分离的物种可以表现出与白色念珠菌的致病协同作用。在目标2中，我们将定义 每种免疫抑制状态下真菌-细菌粘膜生物膜生长的调控机制。 最后，在目标3中，我们将研究非生物群落和宿主反应在粘膜屏障中的作用。 白色念珠菌的侵入和血液传播。拟议的研究有可能导致 临床医生和科学家看待粘膜念珠菌微生物群变化的范式转变 感染。该项目将确定某些口腔细菌为侵袭性真菌的新的、临床相关的媒介。 感染，从而为联合使用抗真菌和抗细菌治疗提供了理由 病人。更好地了解真菌和口腔微生物群之间的关系也可能导致 新的感染风险生物标记物或鉴定益生菌共生体，可以降低感染的可能性 侵袭性黏膜念珠菌病在高危人群中的作用，例如接受重度癌症治疗的患者 化疗。

PROJECT SUMMARY The oral mucosal microbiota is a complex ecosystem primarily represented by bacteria and fungi. Most oropharyngeal fungal infections are caused by the genus Candida and are assumed to result from an overgrowth of indigenous species, primarily C. albicans. C. albicans is a commensal colonizer of the oral mucosa in humans, but is also responsible for infections afflicting immunocompromised hosts. Persistent oropharyngeal thrush is refractory to most antifungals and a significant clinical problem in pharmacologically immunosuppressed patients. Corticosteroid-induced and chemotherapy-induced immunosuppression, are two main risk factors for oropharyngeal candidiasis in humans. C. albicans also causes fungemia, a serious consequence of cancer cytotoxic chemotherapy, which is thought to develop from fungal translocation through compromised mucosal barriers. Changes in endogenous bacterial population size or composition and in the host environment can transform fungal commensals into pathobionts. Work in our previous funding cycle established a synergistic relationship of mitis group streptococci with C. albicans in the pathogenesis of oral candidiasis. We identified mechanisms of synergy which involved both a direct effect on fungal virulence gene expression and a modification of host responses. In this project we will build on our ongoing studies examining the interplay of the resident oral mucosal bacterial microbiota and C. albicans. We will use mouse models of commensal colonization or mucosal infection to interrogate oral bacterial microbiome parameters that promote C. albicans virulence. In aim 1 we will characterize dysbiotic changes in mucosa-associated bacterial communities in oropharyngeal candidiasis, using our established mouse models of cortisone- and chemotherapy-induced immunosuppression. We will then test the hypothesis that certain endogenous bacterial species isolated from dysbiotic states can exhibit pathogenic synergy with C. albicans. In aim 2 we will define the regulatory mechanisms of fungal-bacterial mucosal biofilm growth in each immunosuppression state. Finally, in aim 3 we will examine the role of the dysbiotic communities and host response in mucosal barrier breach and bloodstream dissemination by C. albicans. The proposed studies have the potential to lead to a paradigm shift in how clinicians and scientists view the microbiome changes characterizing mucosal Candida infections. This project will identify certain oral bacteria as new, clinically relevant mediators of invasive fungal infections thus providing justification for the combined use of antifungal and anti-bacterial treatments in at risk patients. A better understanding of the relationship between fungi and the oral microbiome could also result in new biomarkers of infection risk or identification of probiotic commensals that could lower the likelihood of invasive mucosal candidiasis in high-risk populations such as patients undergoing intensive cancer chemotherapy.