POLYOL METABOLITES OF PATHOGENIC FUNGI AS MARKERS FOR INFECTION

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Candida produces large amounts of the polyol D-arabinitol in vitro, and body fluid D-arabinitol levels are high in animals and humans with invasive candidiasis. In preliminary experiments, three pathogenic Aspergillus species and Cryptococcus neoformans produced large amounts of the polyol D-mannitol in vitro, and animals with experimental aspergillosis and cryptococcosis had high body fluid D-mannitol levels. The specific aims of this project are to: 1) evaluate the D-mannitol as a potential quantitative marker for invasive aspergillosis; 2) evaluate D-mannitol as a potential marker for cryptococcosis; and 3) identify polyol products of other pathogenic fungi that may be markers for initial diagnosis, estimating fungal load, and assessing the results of treatment. D-mannitol will be measured by gas chromatography in the serum, urine and homogenized tissues of rats with disseminated and pulmonary aspergillosis: 1) to determine how often and when body fluid and tissue D-mannitol levels rise; 2) to correlate fungal D-mannitol production with severity of infection; and 3) to correlate the effects of antifungal therapy on fungal load and fungal D-mannitol production. D-mannitol will also be measured in sera from: 1) patients receiving intensive chemotherapy for acute leukemia or other neoplastic diseases at several Cincinnati hospitals, 2) all patients who have bone marrow transplants, heart transplants or autopsies at the University of Cincinnati, and 3) patients from our center and others who have proven presence or absence of invasive aspergillosis. D-mannitol will be evaluated as a potential quantitative marker for cryptococcosis by analyzing cerebrospinal fluid (CSF), serum and/or tissues of rabbits with experimental meningeal or disseminated cryptococcosis. The effects of renal failure, meningeal inflammation and antifungal therapy will also be studied. D-mannitol will also be measured in serial serum and/or CSF specimens from all patients with cryptococcosis at the University of Cincinnati, participants in two multicenter trials comparing amphotericin B and fluconazole as initial or maintenance therapies for cryptococcal meningitis, and appropriate controls. Lastly, production of distinctive polyols by other fungi will be studied in vitro, in experimentally infected animals and in humans. The long-term objective of this research is to examine the possibility that detection and quantitation of distinctive microbial metabolites in the body fluids is more broadly applicable as a general strategy for studying infectious diseases.