Virulence of Cryptococcus neoformans. Regulation of capsule synthesis by carbon dioxide.

Granger, Donald L.; Perfect, John R.; Durack, David T.

doi:10.1172/jci112000

Cited by 296 publications

(285 citation statements)

References 18 publications

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“…In addition, the localization of a new structure outside the old one, as seen here, could also be related to the degradation of the initial structure by local factors or by aging. Modifications of the pH through modification in the local CO 2 pressure could affect capsule synthesis 33,34 and perhaps even capsule structure, although this has only been demonstrated in phagosomes. 35 However, it is unlikely that environmental changes are the same in the various organs where capsule structures changes exhibited the same kinetics (brain, cardiac and skeletal muscles, kidney).…”

Section: Discussionmentioning

confidence: 99%

Capsule Structure Changes Associated with Cryptococcus neoformans Crossing of the Blood-Brain Barrier

Charlier

Chrétien

Baudrimont

et al. 2005

The American Journal of Pathology

187

188

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Cryptococcus neoformans is a yeast responsible for disseminated meningoencephalitis in patients with cellular immune defects. The major virulence factor is the polysaccharide capsule. We took advantage of a relevant murine model of disseminated meningoencephalitis to study the early events associated with blood-brain barrier (BBB) crossing. Mice were sacrificed at 1, 6, 24, and 48 hours post-intravenous inoculation, and classical histology, electron microscopy, and double immunofluorescence were used to study tissues and yeasts. Crossing of the BBB occurred early after inoculation, did not involve the choroid plexus but instead occurred at the level of the cortical capillaries, and caused early and severe damage to the structure of the microvessels. Seeding of the leptomeninges was not the primary event but occurred secondary to leakage of cortical pseudocysts. Organ invasion was associated with changes in cryptococcal capsule structure and cell size, which differed in terms of magnitude and kinetics, depending on both the organs involved, and potentially, on the bed structure of the local capillary. The rapid changes in capsule structure could contribute to inability of the host immune response to control cryptococcal infection in extrapulmonary spaces.

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Section: Discussionmentioning

confidence: 99%

Capsule Structure Changes Associated with Cryptococcus neoformans Crossing of the Blood-Brain Barrier

Charlier

Chrétien

Baudrimont

et al. 2005

The American Journal of Pathology

187

188

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“…Cryptococcal cells in lung tissue typically exhibit large capsules (32). Capsule regulation has been associated with virulence for C. neoformans (11), and loss of the ability to increase capsular size results in attenuation (15).…”

Section: Discussionmentioning

confidence: 99%

Effects of Voriconazole on Cryptococcus neoformans

Duin

Cleare

Zaragoza

et al. 2004

Antimicrob Agents Chemother

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Voriconazole is a broad-spectrum triazole that offers extended activity against molds and yeasts that are not susceptible to earlier azole-type drugs. Recent studies indicate that melanization can severely reduce the susceptibility of certain antifungal drugs, but there is no information as to whether voriconazole is vulnerable to this effect. The activity of voriconazole on C. neoformans was assessed by MIC analysis and time-kill assays for melanized and nonmelanized cells. Cell morphology, capsule release, and phagocytosis of C. neoformans were studied in the presence or absence of subinhibitory concentrations of voriconazole. Voriconazole was fungicidal at concentrations of >8 g/ml in vitro against the strains of C. neoformans examined, and its efficacy was not diminished by melanization. Cells grown in subinhibitory concentrations of voriconazole had smaller cellular and capsular volumes than cells grown in the absence of drug. The induction of the capsule by serum was not affected by voriconazole. Cells grown in subinhibitory concentrations of voriconazole released their capsule and were phagocytosed at rates comparable with yeast grown without the antifungal. The high activity of voriconazole against both melanized and nonmelanized cells results suggest that voriconazole may be a particularly valuable drug for cryptococcosis.Cryptococcus neoformans is a relatively frequent cause of serious fungal infections in immunocompromised patients. The prevalence in the United States of cryptococcal meningoencephalitis in patients with AIDS receiving retroviral therapy is currently estimated to be Ͻ2% (23) but is Ͼ30% in areas of South East Asia and Sub-Saharan Africa (29). Patients with AIDS complicated by cryptococcosis often respond poorly to treatment and, in the setting of continued immunosuppression, require lifelong maintenance therapy since currently available antifungal agents seldom eradicate these fungal pathogens in the setting of severe immune suppression (16,41).Voriconazole, a synthetic derivative of fluconazole, is a broad-spectrum triazole antifungal that inhibits cytochrome P450-dependent 14␣-lanosterol demethylation, which is a critical step in fungal cell membrane ergosterol synthesis. Voriconazole demonstrates excellent in vitro activity against C. neoformans (17, 31) and achieves good levels in cerebrospinal fluid (35). Voriconazole is not currently licensed for use in cryptococcosis and no clinical trials have evaluated its efficacy for cryptococcal disease. There is limited published information regarding the clinical use of voriconazole for cryptococcosis (12, 30). In a study by Perfect et al., voriconazole therapy resulted in a 39% response rate in 18 patients with refractory cryptococcal meningoencephalitis (30).Given recent evidence that melanization can significantly reduce the efficacy of certain antifungal drugs against C. neoformans (36), we evaluated the activity of voriconazole against both melanized and nonmelanized yeast cells. Although we previously did not see a protective effect...

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“…Yeast cells used in all experiments were incubated for 4 days at 37°C on a synthetic medium (22) in 5% CO 2 and killed by an overnight incubation with 1.0% formaldehyde. These conditions produce yeast cells with large capsules (23). The cells were then washed with sterile 0.01 M phosphate-buffered 150 mM saline (pH 7.3; PBS) and stored at 4°C.…”

Section: Neoformans Cellsmentioning

confidence: 99%

Biological Correlates of Capsular (Quellung) Reactions ofCryptococcus neoformans

MacGill

Casadevall

et al. 2000

The Journal of Immunology

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The capsular swelling or quellung reaction was reported almost 100 years ago and described the effect of Abs on the appearance of microbial capsules. Despite widespread use to assess Ab binding to capsules, relatively little is known as to the mechanism of this effect or its biological consequences. The fungus Cryptococcus neoformans is an attractive system to study capsule reactions because it has a large polysaccharide capsule that is readily visible by light microscopy. When viewed by differential interference contrast microscopy, binding of mAb to C. neoformans cells produced two distinct capsular reactions that depended on the Ab epitope specificity and the yeast serotype. In the first pattern, termed “rim,” the capsule appears transparent with a highly refractive outer edge. In the second pattern, termed “puffy,” the capsule appears opaque and lacks a highly refractive outer rim. mAbs that bind with a rim pattern suppress the overall rate of C3 deposition on the yeast via the classical and alternative complement pathways. In contrast, mAbs that bind with a puffy pattern do not affect C3 deposition. Protective and nonprotective IgM mAbs produce rim and puffy patterns, respectively. These results indicate that: 1) capsule reactions are a consequence of Ab-induced changes in capsular refractive index; 2) the type of capsule reaction depends on the Ab specificity; and 3) Ab-induced changes in refractive index correlate with biological activities important for host defense against C. neoformans. Our results provide the first evidence associating distinct capsule reaction patterns with Ab biological activity.

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Virulence of Cryptococcus neoformans. Regulation of capsule synthesis by carbon dioxide.

Cited by 296 publications

References 18 publications

Capsule Structure Changes Associated with Cryptococcus neoformans Crossing of the Blood-Brain Barrier

Capsule Structure Changes Associated with Cryptococcus neoformans Crossing of the Blood-Brain Barrier

Effects of Voriconazole on Cryptococcus neoformans

Biological Correlates of Capsular (Quellung) Reactions ofCryptococcus neoformans

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