Oral Epithelial Cells, Candida and PMN Activation

项目摘要 口腔粘膜微生物群是以细菌和真菌为主要代表的复杂生态系统。最 口咽真菌感染是由念珠菌属引起的， 本地种的过度生长，主要是C.白色念珠菌C.白色念珠菌是口腔粘膜的寄生菌， 在人类的粘膜中，它也是感染免疫受损宿主的原因。持久性 口咽鹅口疮对大多数抗真菌药物是无效的， 免疫抑制患者。激素诱导的和化疗诱导的免疫抑制，是两种 人类口咽念珠菌病的主要危险因素。C.白色念珠菌也会引起真菌血症， 癌症细胞毒性化疗的结果，这被认为是从真菌易位， 粘膜屏障受损内源性细菌种群大小或组成的变化以及 宿主环境可以将真菌寄生物转化为致病生物。在我们上一个融资周期的工作 建立了缓症组链球菌与C.白念珠菌在口腔溃疡发病中的作用 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， 表达和宿主反应的修饰。在这个项目中，我们将建立在我们正在进行的研究， 口腔粘膜细菌菌群和C.白色念珠菌我们将使用小鼠模型， 口腔细菌定植或粘膜感染，以询问促进口腔细菌定植或粘膜感染的口腔细菌微生物组参数。 C.白色念珠菌毒力在目标1中，我们将描述粘膜相关细菌的微生态变化， 使用我们建立的可的松小鼠模型， 化疗引起的免疫抑制。然后我们将检验某种内源性细菌 从微生态失调状态分离的物种可以表现出与C.白色念珠菌在目标2中，我们将定义 在每种免疫抑制状态下真菌-细菌粘膜生物膜生长的调节机制。 最后，在目标3中，我们将研究微生态群落和宿主反应在粘膜屏障中的作用。 C.白色念珠菌拟议的研究有可能导致 临床医生和科学家如何看待粘膜念珠菌特征性微生物组变化的范式转变 感染.该项目将确定某些口腔细菌作为新的，临床相关的介质，侵袭性真菌 因此，为风险患者联合使用抗真菌和抗细菌治疗提供了依据。 患者更好地了解真菌和口腔微生物组之间的关系也可能导致 新的感染风险生物标志物或识别益生菌，可以降低感染的可能性。 高危人群中的侵袭性粘膜念珠菌病，如接受强化癌症治疗的患者 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.