CANDIDA ADHERENCE MYCOLOGY RESEARCH UNIT

在全国范围内，念珠菌的血液感染有所增加 到1980年-之间的219%-48%，而这些生物现在占到了10% 所有医院内的血流分离。这一发病率相当于 大肠埃希菌，超过克雷伯氏菌。除了……之外 血源性播散性念珠菌感染，皮肤粘膜念珠菌 感染正变得越来越成问题，特别是在患者中 患有获得性免疫缺陷综合征(艾滋病)；这些患者中有80% 有念珠菌感染。黏附于上皮细胞是第一个 假丝酵母菌的殖民步骤和随后的建立 皮肤粘膜感染。同样，坚持血管内注射 结构被认为是血液流出的关键一步- 从血管内隔室传来的真菌，因为它们是从血液中 感染目标器官。因为与此相关的死亡率 尽管存在念珠菌感染，但念珠菌感染率仍然高得令人不安 具有良好体外抗念珠菌活性的抗真菌药物， 最佳治疗需要增加宿主抵抗力的策略 念珠菌感染(如阻滞性粘连)，联合使用 抗真菌药物。经过二十多年的研究，一位 对念珠菌病的粘连过程的完整理解尚未 进化了。 项目1将利用念珠菌基因组DNA转化为 酿酒酵母及其假丝酵母菌基因表达检测 在酿酒酵母表面的产物鉴定念珠菌粘附素。 项目2将使用在生理学条件下进行的新型体外黏附试验 研究白色念珠菌黏附相互作用的剪切条件 在血液流动过程中放置。项目3将研究一种诱导的疫苗 实验性血液病发病机制的变化 播散性念珠菌病。这项工作将基于以下因素来优化疫苗 念珠菌黏附素及其免疫血清对黏附的影响 以寄生组织。项目4将通过以下方式研究分子机制 哪些白色念珠菌激活补体系统，导致沉积 真菌表面的C3碎片。真菌的影响 表面上的启动、放大和调节机制(S) 将对补体系统的性能进行评估。它的重要性和 C3对白念珠菌黏附的贡献将通过 使用体外和体内系统的研究单位的其他成员。 项目5将通过功能分离编码细胞表面蛋白的基因 分泌缺陷报告基因的互补。这些基因 调节以响应已知的环境信号来改变 念珠菌细胞表面将通过差异杂交进行鉴定 放映。这个基因子集的结构和功能将是 通过基因和生物化学方法的组合进行探索。

Nationwide, bloodstream infections with Candida species have increased by 219-48% between 1980-1989, and these organisms now account for 10% of all nosocomial bloodstream isolates. This incidence equals that of Escherichia coli and surpasses Klebsiella species. In addition to hematogenously disseminated candidal infections, mucocutaneous candidal infections are becoming increasingly problematic, especially in patients with the acquired immunodeficiency syndrome (AIDS); 80% of these patients have candidal infections. Adherence to epithelial cells is the first step in colonization by Candida and subsequent establishment of mucocutaneous infection. Similarly, adherence to intravascular structures is considered to be a critical step in the egress of blood- borne fungi from the intravascular compartment, as they hematogenously infect target organs. Because the mortality rates associated with candidal infections remain disturbingly high despite the presence of antifungal agents with excellent in vitro activity against Candida, optimal therapy requires strategies to increase host resistance to candidal infection (such as blocking adherence), combined with the use of antifungal agents. After more than two decades of study, a single integrated understanding of the adhesive process in candidiasis has not evolved. Project 1 will use transformation of candidal genomic DNA into Saccharomyces cerevisiae and assays of expression of candidal gene products at the surface of S. cerevisiae to identify candidal adhesins. Project 2 will use novel in vitro adhesion assays done under physiologic shear conditions to study C. albicans adhesive interactions which take place during blood flow. Project 3 will investigate a vaccine induced alteration in the pathogenesis of experimental hematogenously disseminated candidiasis. This work will optimize a vaccine based on candidal adhesins and determine the effects of immune serum on adherence to host tissue. Project 4 will investigate the molecular mechanisms by which C. albicans activates the complement system, leading to deposition of C3 fragments on the fungal surface. The influence of the fungal surface on the mechanism(s) for initiation, amplification and regulation of the complement system will be evaluated. The importance and contributions of C3 to adhesion of C. albicans will be evaluated by the other members of the Research Unit using in vitro and in vivo systems. Project 5 will isolate genes encoding cell surface proteins by functional complementation of a secretory-defective reporter gene. Those genes regulated in response to environmental signals known to alter the candidal cell surface will be identified by differential hybridization screening. The structure and function of this subset of genes will be explored by a combination of genetic and biochemical approaches.