C. Neoformans Infection in Organ Transplant Recipients

描述（由申请人提供）： 器官移植受者已经成为一个领先的和不断增长的群体免疫功能低下的患者隐球菌病的风险。移植受者使用的免疫抑制剂在体外对C.新人类现有数据表明，隐球菌病的谱、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]。移植受者隐球菌分离株是否代表免疫抑制药物耐药突变体尚不清楚。基因突变赋予免疫抑制药物耐药性，血清型，或其他毒力因子的影响。新生儿对移植受者的组织嗜性和结果的影响尚未阐明。最后，还不知道C.在移植受者中的新生儿代表潜伏感染的重新激活或新的获得。本研究的主要目的是：确定接受他克莫司、环孢霉素或雷帕霉素的移植受者中隐球菌病的临床表现和结局是否存在差异，并评估脑脊液中免疫抑制剂水平是否与中枢神经系统感染相关。2.确定C.移植受者中的新型隐球菌分离株代表免疫抑制剂抗性突变体的突破性感染，并比较突变体与非突变体隐球菌分离株的临床表现、对治疗的反应和结果。3.为确定C.新生儿与临床表现和结果相关：包膜形成、血清型、黑色素合成、热敏感性、尿素酶和磷脂酶产生。4.确定C.新型链球菌代表潜伏感染或新获得的再激活，并辨别某些蛋白质印迹条带模式是否比其他条带模式更可能再激活。本研究将调查真菌感染菌株的分子策略与临床结果相结合。关于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。新人类鉴定的毒力因子可作为新的治疗方式的分子靶点。最后，关于再激活或原发感染的数据对预防C.移植受者中的新生儿感染。

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.