C. Neoformans Infection in Organ Transplant Recipients

描述(由申请人提供)： 器官移植接受者已经成为免疫功能低下的患者中面临隐球菌病风险的一个主要且不断增长的群体。移植受者使用的免疫抑制剂在体外对新生葡萄球菌有抗真菌作用。现有数据表明，隐球菌病的光谱、类型或表现可能会因主要免疫抑制药物的抗真菌作用而改变[Husain 00]。移植受者中的隐球菌分离株是否代表免疫抑制药物耐药突变尚不清楚。导致免疫抑制药物耐药性、血清型或其他毒力因素的基因突变对移植受者的组织趋向性和预后的影响尚未阐明。最后，尚不清楚移植受者体内的新生芽孢杆菌是否代表潜伏感染或新的获得性感染的重新激活。该研究的主要目的是：确定接受他克莫司、环孢素或雷帕霉素的移植受者是否存在临床表现和隐球菌病结局的差异，并评估免疫抑制剂的脑脊液水平是否与中枢神经系统感染相关。2.确定移植受者中的新生隐球菌是否代表免疫抑制剂耐药突变株的突破性感染，并比较突变株和非突变株的临床表现、治疗反应和转归。3.确定新生葡萄球菌的以下特征是否与临床表现和转归相关：被膜形成、血清型、黑色素合成、热敏性、尿素酶和磷脂酶产生。4.确定新生芽孢杆菌是否代表潜伏感染或新感染的重新激活，并辨别某些Western印迹条带是否比其他条带更有可能重新激活。这项研究将研究真菌感染菌株的分子策略与临床结果结合起来。有关突变的知识不仅具有病理生理学意义，而且具有潜在的深远的治疗意义，对新生葡萄球菌的管理具有重要意义。已确定的毒力因子可能作为新的治疗方式的分子靶点。最后，关于再次激活或初次感染的数据对预防移植受者的新生葡萄球菌感染具有重要意义。

DESCRIPTION (provided by applicant): Organ transplant recipients have emerged as a leading and growing group of immunocompromised patients at risk for cryptococcosis. The immunosuppressive agents employed in transplant recipients have antifungal in vitro against C. neoformans. Existing data suggest that the spectrum, type, or presentation of cryptococcosis might be altered by the antifungal effects of primary immunosuppressive drugs [Husain 00]. Whether cryptococcal isolates in transplant recipients represent immunosuppressive drug resistant mutants is not known. The impact of gene mutations conferring immunosuppressive drug resistance, serotype, or other virulence factors of C. neoformans on tissue tropism and outcome in transplant recipients has not been elucidated. Finally, it is not known whether C. neoformans in transplant recipient represents reactivation of a latent infection or a new acquisition. The primary objectives of the study are: To determine if there are differences in clinical manifestations and outcome of cryptococcosis in transplant recipients receiving tacrolimus, cyclosporine, or rapamycin, and to assess whether cerebrospinal fluid levels of immunosuppressive agents correlate with central nervous system infection. 2.To determine if C. neoformans isolates in transplant recipients represent breakthrough infections with immunosuppressive agent resistant mutants and to compare the clinical manifestations, response to therapy, and outcome of mutant versus non-mutant cryptococcal isolates. 3. To determine whether the following characteristics of C. neoformans correlate with clinical manifestations and outcome: capsule formation, serotype, melanin synthesis, thermal susceptibility, urease, and phospholipase production. 4. To determine if C. neoformans represents reactivation of a latently harbored infection or a new acquisition and to discern if certain Western blot band patterns are more likely to reactivate than others. This study merges the molecular strategy of investigating the infecting strains of the fungus with clinical outcome. Knowledge regarding mutations has not only pathophysiologic, but potentially profound therapeutic, implications for the management of C. neoformans. The virulence factors identified may serve as molecular targets for novel therapeutic modalities. Finally, the data regarding reactivation or primary infection has implications relevant for the prevention of C. neoformans infection in transplant recipients.