Oral Epithelial Cells, Candida and PMN Activation

口腔上皮细胞、念珠菌和 PMN 激活

• 批准号: 7932529
• 负责人: Anna I Dongari-Bagtzoglou
• 金额: $ 21.34万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932529
• 关键词: Accounting; Address; Affect; Anti-Infective Agents; Antifungal Agents; Attenuated; Biological Models; Candida; Candida albicans; Candidiasis; Cells; Characteristics; Child; Complex; Data; Defense Mechanisms; Development; Disease; Environment; Epithelial Cells; Esophageal mucous membrane; Event; Extracellular Matrix; Funding; Gastrointestinal tract structure; Genes; Goals; Grant; HIV; Histologic; Host Defense; Human; Immune; Immune Cell Activation; Immune response; Immune system; Immunocompromised Host; In Situ; In Vitro; Individual; Infection; Inflammatory Response Pathway; Investigation; Knowledge; Lead; Lesion; Malignant Neoplasms; Microbial Biofilms; Modeling; Molecular; Monitor; Mucous Membrane; Mycoses; Nature; Oral; Oral candidiasis; Oral cavity; Oral mucous membrane structure; Organism; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Prevention; Proteins; Public Health; Regulation; Research; Role; Staging; Stratified Epithelium; Surface; System; Testing; Tissue Model; Tissues; Virulence Factors; Work; analog; candida biofilm; cellular development; cytokine; dectin 1; design; in vivo; monolayer; mouse model; mucosal site; neonate; neutrophil; new therapeutic target; oral cavity epithelium; oral infection; oral tissue; paracrine; pathogen; peripheral blood; polarized cell; prevent; receptor; receptor expression; response; soft tissue; tool

DESCRIPTION (provided by applicant): Oral thrush (pseudomembranous candidiasis) continues to afflict an unacceptably high percentage of immunocompromised individuals, particularly children. Since the recalcitrant nature of this oral infection, triggered primarily by C. albicans, could be attributed to its biofilm forming activities, knowledge of the distinct stages in mucosal biofilm formation and concomitant host responses is of paramount importance in understanding the pathogenesis of this infection and designing effective anti-infective strategies. The goals of the proposed studies in the next competitive cycle are directed toward a better understanding of the host response to mucosal biofilms formed by Candida in the oral cavity and the role of proinflammatory cytokines and neutrophils in the prevention or elimination of such biofilms. In the current funding cycle we established a three-dimensional oral tissue model which faithfully reproduces the histologic and cellular characteristics of pseudomembranous candidiasis lesions and incorporated neutrophils so that we can examine their candidacidal activities in situ. While working with this tissue analogue we discovered that Candida does not interact with oral mucosal tissues as single cell organisms, but forms a complex mucosal biofilm. We were able to reproduce and validate the presence of a mucosal tissue biofilm in a mouse model of oroesophageal candidiasis. This application will build on data generated during the current funding cycle to address the following Aims: a) characterize the stages in development, cellular composition and spatial arrangement of biofilms in the oral mucosa and test the hypothesis that Candida tissue biofilms affect the mucosal proinflammatory cytokine response to infection; b) test the hypothesis that neutrophil anti-Candida responses are inhibited within the biofilm environment and examine the mechanisms of this inhibition; and c) investigate the role of specific Candida gene products in facilitating oral mucosal biofilm formation, tissue invasion and damage. Since superficial mycoses characterized by Candida biofilm formation on the surface of stratified epithelia affect other GI tract mucosal sites, such as the esophageal mucosa, which may be more vulnerable to invasion our studies may have far reaching implications in preventing disseminated infection. We envision that our studies will lead to the development of new oral anti-mycotic agents which target pathways of mucosal biofilm regulation by C. albicans and promote local neutrophil antifungal functions. Public Health Significance: Oral pseudomembranous candidiasis is still the most prevalent form of Candida infection in patients with weakened or immature immune systems, such as HIV+ children, neonates and patients with malignancies. We propose that in this infection biofilms provide a protective environment for Candida from innate defense mechanisms, which may promote its persistence. We envision that our studies in tissue biofilms will lead to the development of new oral anti-mycotic agents which target pathways of biofilm regulation by C. albicans and promote neutrophil antifungal functions.

描述（由申请人提供）：口服鹅口疮（假念珠菌病）继续使免疫力低下的个体（尤其是儿童）遭受不可接受的高百分比。由于主要由白色念珠菌触发的这种口腔感染的顽固性可以归因于其生物膜的形成活性，因此了解粘膜生物膜形成的不同阶段的知识和伴随宿主反应对理解这种感染和设计有效的抗抗抗反感策略的病原体具有至关重要的重要性。下一个竞争周期中提出的研究的目标是针对念珠菌在口腔中形成的对粘膜生物膜的反应以及促炎性细胞因子和中性粒细胞在预防或消除这种生物膜中的作用。在当前的融资周期中，我们建立了一个三维的口腔组织模型，该模型忠实地再现了假膜状念珠菌病变的组织学和细胞特征，并掺入了嗜中性粒细胞，以便我们可以检查他们的念珠菌活性。在与该组织类似物的过程中，我们发现念珠菌不与口服粘膜组织作为单细胞生物相互作用，而是形成复杂的粘膜生物膜。我们能够繁殖并验证粘液性念珠菌病小鼠模型中粘膜组织生物膜的存在。该应用将建立在当前资金周期中生成的数据以解决以下目的的基础： b）检验以下假设：中性粒细胞抗candida反应在生物膜环境中受到抑制并检查这种抑制作用的机制； c）研究特定念珠菌基因产物在促进口服粘膜生物膜形成，组织侵袭和损伤中的作用。由于分层上皮表面上以念珠菌生物膜形成为特征的浅表真皮会影响其他胃肠道粘膜位点，例如食管粘膜，这可能更容易受到侵袭的影响，我们的研究可能对预防传播感染具有很大的影响。我们设想我们的研究将导致新的口服抗肌动物剂的发展，这些抗菌丝剂靶向粘膜生物膜对白色念珠菌调节的途径并促进局部嗜中性粒细胞抗真菌功能。公共卫生的意义：口服假性念珠菌病仍然是弱或不成熟免疫系统的患者（例如HIV+儿童，新生儿和恶性肿瘤患者）中最普遍的念珠菌感染形式。我们建议，在这种感染中，生物膜为先天防御机制提供了念珠菌的保护环境，这可能会促进其持久性。我们设想我们在组织生物膜方面的研究将导致新的口服抗肿瘤剂的发展，这些抗肌膜针对白色念珠菌调节生物膜的途径并促进中性粒细胞抗真菌功能。