<i>Cryptococcus neoformans</i>Is a Facultative Intracellular Pathogen in Murine Pulmonary Infection

Feldmesser, Marta; Kress, Yvonne; Novikoff, Phyllis M.; Casadevall, Arturo

doi:10.1128/iai.68.7.4225-4237.2000

Cited by 411 publications

(451 citation statements)

References 56 publications

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“…Isc1 REGULATES NEUROTROPISM OF CRYPTOCOCCUS NEOFORMANS 5985 phagolysosomes (13,44). Our studies show that Isc1 is important for C. neoformans to survive intracellularly.…”

Section: Vol 74 2006mentioning

confidence: 73%

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The Cryptococcal Enzyme Inositol Phosphosphingolipid-Phospholipase C Confers Resistance to the Antifungal Effects of Macrophages and Promotes Fungal Dissemination to the Central Nervous System

Shea¹,

Kechichian²,

Luberto³

et al. 2006

Infect Immun

104

108

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In recent years, sphingolipids have emerged as critical molecules in the regulation of microbial pathogenesis. In fungi, the synthesis of complex sphingolipids is important for the regulation of pathogenicity, but the role of sphingolipid degradation in fungal virulence is not known. Here, we isolated and characterized the inositol phosphosphingolipid-phospholipase C1 (ISC1) gene from the fungal pathogen Cryptococcus neoformans and showed that it encodes an enzyme that metabolizes fungal inositol sphingolipids. Isc1 protects C. neoformans from acidic, oxidative, and nitrosative stresses, which are encountered by the fungus in the phagolysosomes of activated macrophages, through a Pma1-dependent mechanism(s). In an immunocompetent mouse model, the C. neoformans ⌬isc1 mutant strain is almost exclusively found extracellularly and in a hyperencapsulated form, and its dissemination to the brain is remarkably reduced compared to that of control strains. Interestingly, the dissemination of the C. neoformans ⌬isc1 strain to the brain is promptly restored in these mice when alveolar macrophages are pharmacologically depleted or when infecting an immunodeficient mouse in which macrophages are not efficiently activated. These studies suggest that Isc1 plays a key role in protecting C. neoformans from the intracellular environment of macrophages, whose activation is important for preventing fungal dissemination of the ⌬isc1 strain to the central nervous system and the development of meningoencephalitis.

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“…Isc1 REGULATES NEUROTROPISM OF CRYPTOCOCCUS NEOFORMANS 5985 phagolysosomes (13,44). Our studies show that Isc1 is important for C. neoformans to survive intracellularly.…”

Section: Vol 74 2006mentioning

confidence: 73%

“…J774.16 is a murine reticulum sarcoma macrophage-like cell line that is well characterized (7) and is extensively used as a model for cryptococcal interactions with macrophages (13,44). J774.16 cells were used up to passage 10, with each passage dilution equal to 1:12.…”

Section: Fig 2 Deletion and Reconstitution Of Isc1 In C Neoformansmentioning

confidence: 99%

The Cryptococcal Enzyme Inositol Phosphosphingolipid-Phospholipase C Confers Resistance to the Antifungal Effects of Macrophages and Promotes Fungal Dissemination to the Central Nervous System

Shea¹,

Kechichian²,

Luberto³

et al. 2006

Infect Immun

104

108

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“…During infection, cryptococcal polysaccharide accumulates in tissues (14). Released polysaccharide is a potent immunomodulator (37) and toxic to phagocytic cells (10). Previous studies have shown that subinhibitory concentrations of amphotericin B and fluconazole increase capsular release (27).…”

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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“…The main component of the capsule is glucuronoxylomannan (GXM), 3 which is antiphagocytic in vitro and has been demonstrated to cause a variety of deleterious effects to immune function (1). Despite its antiphagocytic properties in vitro, C. neoformans is a facultative intracellular pathogen in vivo (3). Although it is a relatively rare cause disease in normal individuals, C. neoformans is a relatively frequent cause of chronic meningitis in patients with impaired immune function (reviewed in Ref.…”

Section: Ryptococcus Neoformans Is the Only Pathogenic Fungusmentioning

confidence: 99%

Immunoglobulin M Efficacy AgainstCryptococcus neoformans: Mechanism, Dose Dependence, and Prozone-Like Effects in Passive Protection Experiments

Taborda

Casadevall

2001

The Journal of Immunology

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The IgM mAbs 12A1 and 13F1 are protective and nonprotective, respectively, against lethal Cryptococcus neoformans infection in mice. To better understand the variables that contribute to IgM efficacy against C. neoformans, we studied the effects of inoculum size, route of infection, and Ab dose for each of these mAbs. mAb 13F1 did not prolong survival under any condition studied. mAb 12A1 prolonged survival after the administration of certain Ab doses after i.p. infection with defined inocula and promoted phagocytosis, agglutination, and the formation of inflammatory cell rings around yeast cells in vivo. Large Ab doses of mAb 12A1 resulted in either no protection or enhanced infection, consistent with a prozone-like effect. Investigation of this phenomenon revealed that the fungal cell was protected against microbicidal nitrogen-derived oxidants when large amounts of Ab were bound to the C. neoformans capsule. mAb 12A1 was opsonic in vitro for peritoneal, but not splenic or alveolar macrophages. In summary, our results indicate that IgM efficacy against C. neoformans is a function of the route of infection, inoculum, and Ab dose and is associated with its ability to promote opsonization, agglutination, and phagocytic ring formation in vivo. The occurrence of the prozone-like phenomenon implies that high Ab titers are not necessarily beneficial in assuring protection against certain pathogens and that caution should be exercised in using high Ab titer as a measure for vaccine efficacy.

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Cryptococcus neoformansIs a Facultative Intracellular Pathogen in Murine Pulmonary Infection

Cited by 411 publications

References 56 publications

The Cryptococcal Enzyme Inositol Phosphosphingolipid-Phospholipase C Confers Resistance to the Antifungal Effects of Macrophages and Promotes Fungal Dissemination to the Central Nervous System

The Cryptococcal Enzyme Inositol Phosphosphingolipid-Phospholipase C Confers Resistance to the Antifungal Effects of Macrophages and Promotes Fungal Dissemination to the Central Nervous System

Effects of Voriconazole on Cryptococcus neoformans

Immunoglobulin M Efficacy AgainstCryptococcus neoformans: Mechanism, Dose Dependence, and Prozone-Like Effects in Passive Protection Experiments

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