IMMUNE RECOGNITION OF CANDIDA--ROLE OF CELL WALL

描述（逐字来自申请人的摘要）：病原性真菌，例如 白色念珠菌作为机会致病菌越来越常见， 在免疫受损的宿主中引起显著的发病率和死亡率。 尽管真菌病原体的重要性越来越大，但仍有许多问题没有得到解决。 了解其发病机制。具体而言，尚不清楚如何 真菌病原体与先天免疫系统的细胞成分相互作用。 真菌病原体与先天性 免疫系统决定了感染是否会发展成全身性的。 葡聚糖是葡萄糖的（1-3）-β-D-连接的聚合物，其主要是 真菌细胞壁的碳水化合物成分。葡聚糖也被释放到 真菌感染患者的体循环。我们的工作 假设假丝酵母细胞壁（1-3）-β-D-葡聚糖在 免疫感受态细胞，即巨噬细胞识别念珠菌， 中性粒细胞为了批判性地评估这一假设，有四个具体的 目标。I.我们将分离和化学表征（1-3）-β-D-葡聚糖， 假丝酵母细胞壁、来自假丝酵母菌丝的葡聚糖和 作为外聚合物释放到细胞外环境中。二.我们将描述 念珠菌衍生受体介导的结合/内化 （1-3）-β-D-葡聚糖在人类巨噬细胞和中性粒细胞，并确定是否 葡聚糖受体介导念珠菌的摄取和/或杀灭。这些 研究还将解决念珠菌葡聚糖是否 被巨噬细胞上的CR 3（CD 11b/CD 18）和/或Toll样受体识别 和中性粒细胞。三.我们将研究念珠菌的体外作用 葡聚糖对转录调节蛋白（NFkB和NF-IL 6）活化的影响 以及人类巨噬细胞中炎症细胞因子和趋化因子的表达 和中性粒细胞。四.我们将研究念珠菌衍生物在体内的作用， 转录激活蛋白NFkB和NF-IL 6上的（1-3）-β-D-葡聚糖， 免疫调节和炎症介质的表达，TH 1/TH 2转换 以及假丝酵母葡聚糖是否能抵御真菌的攻击。我们将 还比较和对比念珠菌衍生的葡聚糖和甘露聚糖在 为了确定是否有差异，在响应这两个 真菌细胞壁的常见成分。我们的长远目标是 确定真菌细胞壁碳水化合物的细胞和分子机制 在真菌感染的发病机理中， 鉴定潜在的药物靶点和/或改进的治疗策略， 真菌性败血症的治疗

DESCRIPTION (Verbatim from Applicant's Abstract): Pathogenic fungi, such as Candida albicans, are increasingly common as opportunistic pathogens which cause significant morbidity and mortality in the immunocompromised host. Despite the growing significance of fungal pathogens there is much that is not known about their mechanisms of pathogenesis. Specifically, it is not clear how fungal pathogens interact with cellular components of the innate immune system. It is highly probable that the interaction of fungal pathogens with the innate immune system determines whether the infection proceeds to become systemic. Glucans are (1-3)-beta-D-linked polymers of glucose which are major carbohydrate constituents of fungal cell walls. Glucans are also released into the systemic circulation of patients with fungal infections. Our working hypothesis is that Candida cell wall (1-3)-beta-D-glucans play a major role in the recognition of Candida by immune competent cells, i.e. macrophages and neutrophils. To critically evaluate this hypothesis there are four specific aims. I. We will isolate and chemically characterize (1-3)-beta-D-glucans from Candida cell walls, glucans from Candida hyphae and the glucans which are released into the extracellular milieu as exopolymers. II. We will characterize the receptor mediated binding/internalization of Candida derived (1-3)-beta-D-glucans in human macrophages and neutrophils and determine whether the glucan receptor(s) mediate the uptake and/or killing of Candida. These studies will also address the questions of whether Candida glucans are recognized by the CR3 (CD11b/CD18) and/or Toll-like receptors on macrophages and neutrophils. III. We will investigate the in vitro effect of Candida glucans on activation of transcriptional regulatory proteins (NFkB and NF-IL6) and expression of inflammatory cytokines and chemokines in human macrophages and neutrophils. IV. We will investigate the in vivo effect of Candida derived (1-3)-beta-D-glucans on the transcriptional activator proteins NFkB and NF-IL6, expression of immunoregulatory and inflammatory mediators, TH1/TH2 switching and whether Candida glucans will protect against a fungal challenge. We will also compare and contrast the effects of Candida derived glucans and mannans in order to determine whether there are differences in response to these two common constituents of fungal cell walls. Our long-term objectives are to define the cellular and molecular mechanisms of fungal cell wall carbohydrates in the pathogenesis of fungal infections and to utilize this basic science data to identify potential drug targets and/or improved therapeutic strategies for the management of fungal sepsis.