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Production of the hexitol D-mannitol by Cryptococcus neoformans in vitro and in rabbits with experimental meningitis
1Department of Internal Medicine, University of Cincinnati College of Medicine, Ohio.
Abstract:
We studied the ability of Cryptococcus neoformans to produce the hexitol D-mannitol in vitro and in rabbits with experimental meningitis. Twelve of twelve human isolates of C. neoformans produced D-mannitol in yeast nitrogen base plus 1% glucose and released D-mannitol into the medium. In a pilot study, pooled cerebrospinal fluid (CSF) from cortisone-treated rabbits given 3 x 10(7) C. neoformans H99 intracisternally contained more D-mannitol (identified by gas chromatography and enzymatically) than CSF from normal controls or cortisone-untreated rabbits with self-limited meningitis. In a second experiment, cortisone-treated rabbits given C. neoformans intracisternally had significantly higher CSF D-mannitol concentrations than controls given cortisone alone at 4, 6, and 8 days after infection. Moreover, log10 CSF D-mannitol correlated well with log10 CSF CFU (r = 0.81) and log10 CSF cryptococcal antigen titers (r = 0.78). Lastly, the initial volume of distribution and elimination half-life of D-mannitol given intracisternally to normal rabbits suggested that D-mannitol was distributed in total CSF and was removed by CSF bulk flow. Thus, C. neoformans produces D-mannitol in vitro and in vivo, and D-mannitol is a quantitative marker for experimental cryptococcal meningitis. D-Mannitol produced by C. neoformans may also contribute to brain edema and interfere with phagocyte killing by scavenging hydroxyl radicals.
Insights
Cryptococcus neoformans produces D-mannitol in vitro and in rabbits with experimental meningitis. This D-mannitol serves as a quantitative marker for cryptococcal meningitis, potentially contributing to brain edema.
Area of Science:
- Mycology
- Infectious Diseases
- Biochemistry
Background:
- Cryptococcus neoformans is a fungal pathogen causing meningitis.
- The role of D-mannitol production by C. neoformans in infection is not well understood.
Purpose of the Study:
- To investigate the in vitro and in vivo production of D-mannitol by Cryptococcus neoformans.
- To evaluate D-mannitol as a potential biomarker for experimental cryptococcal meningitis.
Main Methods:
- In vitro studies of C. neoformans isolates in glucose-rich media.
- Intracisternal inoculation of C. neoformans in cortisone-treated rabbits to induce meningitis.
- Cerebrospinal fluid (CSF) analysis for D-mannitol, fungal load (CFU), and cryptococcal antigen.
- Pharmacokinetic analysis of D-mannitol in rabbit CSF.
Main Results:
- All tested C. neoformans isolates produced and released D-mannitol in vitro.
- CSF D-mannitol levels were significantly elevated in rabbits with experimental cryptococcal meningitis compared to controls.
- CSF D-mannitol concentrations correlated strongly with fungal burden and antigen titers.
- D-mannitol distribution and elimination in CSF suggested bulk flow clearance.
Conclusions:
- Cryptococcus neoformans produces D-mannitol both in vitro and during experimental meningitis in rabbits.
- D-mannitol is a reliable quantitative marker for experimental cryptococcal meningitis.
- Produced D-mannitol may contribute to pathogenesis, including brain edema and impaired phagocyte function.