CANDIDA ADHERENCE MYCOLOGY RESEARCH UNIT

念珠菌粘附真菌学研究单位

• 批准号: 2004191
• 负责人: John E Edwards
• 金额: $ 54.02万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-01 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2004191
• 关键词: Candida albicans; candidiasis; cell adhesion; host organism interaction

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.

在全国范围内，念珠菌属的血流感染有所增加 在1980-1989年之间增加了219-48%，这些生物现在占10%， 所有医院血液分离物 这个发生率等于 大肠埃希菌和克雷伯菌属。 除了 血源性播散性念珠菌感染，粘膜皮肤念珠菌 感染正变得越来越成问题，特别是在患者中， 获得性免疫缺陷综合征（艾滋病）; 80%的患者 有念珠菌感染 粘附于上皮细胞是第一位的 假丝酵母定殖步骤和随后建立 皮肤粘膜感染 同样，血管内粘附 结构被认为是血液流出的关键步骤- 从血管内室携带真菌，因为它们是造血的， 感染目标器官 因为死亡率与 念珠菌感染仍然令人不安的高，尽管存在 具有优异的抗念珠菌体外活性的抗真菌剂， 最佳的治疗需要增加宿主抵抗力的策略 念珠菌感染（如粘连阻塞），结合使用 抗真菌剂。 经过二十多年的研究， 对念珠菌病的粘附过程的全面了解还没有 进化了 项目1将使用念珠菌基因组DNA转化为 酿酒酵母及其念珠菌基因表达检测 S.酿酒酵母来鉴定念珠菌粘附素。 项目2将使用在生理条件下进行的新型体外粘附试验 剪切条件下研究C.白色念珠菌粘附相互作用， 在血液流动中。 项目3将研究一种疫苗， 实验性造血干细胞移植的发病机制改变 播散性念珠菌病 这项工作将优化疫苗的基础上， 念珠菌粘附素，并确定免疫血清对粘附的影响 宿主组织 项目4将研究分子机制， 其中C。白色念珠菌激活补体系统，导致沉积 真菌表面的C3片段 真菌的影响 启动、扩增和调节机制的表面 将对补体系统进行评估。 的重要性和 C3对C.白色念珠菌将由 研究单位的其他成员使用体外和体内系统。 项目5将分离编码细胞表面蛋白的基因， 分泌缺陷型报告基因的互补。 这些基因 调节以响应已知改变环境信号的环境信号， 通过差异杂交鉴定念珠菌细胞表面 筛选 这一基因子集的结构和功能将是 通过遗传学和生物化学方法的结合来探索。