Oral Epithelial Cells, Candida and PMN Activation

描述（由申请方提供）：鹅口疮是一种粘膜生物膜感染，持续困扰着不可接受的高比例免疫功能低下个体，特别是新生儿和接受免疫抑制药物治疗的患者。虽然C.白色念珠菌是主要的病原体，这种感染的微生物生态学是复杂的，因为它含有内源性细菌植物群的成员。念珠菌与链球菌在人类口腔中形成混合生物膜，但这些生物膜在粘膜相关或侵袭性感染过程中的作用尚不清楚。在建议的工作C。albicans和S.口腔念珠菌将被用作模式生物，以研究非致病性口腔细菌植物群与已建立毒力的机会性真菌（如C.白色念珠菌 我们的研究依赖于一个系统和全面的方法来表征宿主和病原体介导的混合机会性粘膜感染的发病机制。我们假设增强的促炎宿主反应和增加的念珠菌毒力介导这些微生物在口腔和食管粘膜中的致病协同作用。在目标I中，我们将描述链球菌对TLR 2/4介导的宿主对混合感染的反应的影响，并测试夸大的促炎性和嗜中性反应混合的链球菌生物膜导致病理学增加的假设。在目标II中，我们将研究混合微生物群落组装和毒力的机制。链球菌葡糖基转移酶的作用，主要酶有助于细胞外粘液，促进生物膜，将被检查。In C.我们将鉴定控制双群落装配的转录因子。我们还将检验S. oralis增强了C.使用小鼠口腔共感染模型，通过调节几个Rim 101依赖性毒力基因（在口腔粘膜侵袭中很重要）来抑制白色念珠菌。了解口腔链球菌对念珠菌毒力和粘膜炎症反应的影响，将为口腔和食管宿主生态位内真菌感染的发病机制提供重要的新见解。更重要的是，发现口腔细菌在发病机制中的协同作用， 可能对目前仅基于抗真菌药的鹅口疮的治疗具有重要的临床意义。

DESCRIPTION (provided by applicant): Oral thrush, a mucosal biofilm infection, continues to afflict an unacceptably high percentage of immunocompromised individuals, particularly neonates and patients on immunosuppressive medications. Although C. albicans is the primary etiologic pathogen, the microbial ecology of this infection is complex since it contains members of the endogenous bacterial flora. Candida forms mixed biofilms with streptococci in the oral cavities of humans but the role of these biofilms during the course of mucosa-associated or invasive infections is unknown. In the proposed work C. albicans and S. oralis will be used as model organisms to study the mucosal disease-promoting interactions of the non-pathogenic oral bacterial flora with opportunistic fungi that have established virulence, such as C. albicans. Our studies rely upon a systematic and comprehensive approach to characterize both host- and pathogen-mediated aspects of the pathogenesis of mixed opportunistic mucosal infections. We hypothesize that enhanced proinflammatory host responses and increased Candida virulence mediate a pathogenic synergy of these microorganisms in the oral and esophageal mucosa. In aim I we will characterize the influence of streptococci on the TLR2/4-mediated host response to mixed infection and test the hypothesis that the exaggerated proinflammatory and neutrophilic response to mixed Candida-streptococcal biofilms leads to increased pathology. In aim II we will examine mechanisms of mixed microbial community assembly and virulence. The role of streptococcal glucosyltransferases, major enzymes contributing to the extracellular slime that promotes biofilms, will be examined. In C. albicans we will identify the transcription factor(s) tht control dual community assembly. We will also test the hypothesis that S. oralis increases the virulence of C. albicans by modulating several Rim101-dependent virulence genes, important in oral mucosal invasion, using a mouse oral co-infection model. An understanding of the effects of oral streptococci on Candida virulence and the mucosal inflammatory response will provide important novel insights into the pathogenesis of fungal infection within the oral and esophageal host niche. More importantly, the discovery of a synergistic role for oral bacteria in pathogenesis may have important clinical implications in the treatment of oral thrush which is currently based solely on antifungals.