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.
|Effective start/end date||4/15/03 → 3/31/06|
- University of Pittsburgh (107042-A01 // 5 R01 AI054719-03)
- National Institute of Allergy and Infectious Diseases (107042-A01 // 5 R01 AI054719-03)