Decreased virulence in stable, acapsular mutants ofCryptococcus neoformans

Fromtling, Robert A.; Shadomy, H. Jean; Jacobson, Eric S.

doi:10.1007/bf00636177

Cited by 184 publications

(141 citation statements)

References 12 publications

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“…heightened significance of ROS in conferring protection to this species. The capsule surrounding the Cryptococcus renders the pathogen less susceptible to phagocytosis and so may deprive ROS accessibility to the fungus (3,40,41). C. neoformans also has the potential to elicit deposition of opsonins, which may trigger the phagocyte respiratory burst, at sites below the capsule surface, where they will be incapable of binding complement or FcRs on the surface of myeloid cells (3,42).…”

Section: Discussionmentioning

confidence: 99%

In the Absence of Reactive Oxygen Species, T Cells Default to a Th1 Phenotype and Mediate Protection against Pulmonary Cryptococcus neoformans Infection

Snelgrove

Edwards

Williams

et al. 2006

The Journal of Immunology

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In recent years, the prevalence of invasive fungal infections has increased, attributed mostly to the rising population of immunocompromised individuals. Cryptococcus neoformans has been one of the most devastating, with an estimated 6–8% of AIDS-infected patients succumbing to Cryptococcus-associated meningitis. Reactive oxygen species (ROS) are potent antimicrobial agents but also play a significant role in regulating immune cell phenotype, but cause immunopathology when produced in excess. We now show that mice lacking phagocyte NADPH oxidase have heightened macrophage and Th1 responses and improved pathogen containment within pulmonary granulomatous lesions. Consequently, dissemination of this fungus to the brain is diminished, an effect that is independent of IL-12. Similar results are described using the metalloporphyrin antioxidant manganese(III) tetrakis(N-ethyl pyridinium-2-yl)porphyrin, which also promoted a protective Th1 response and reduced dissemination to the brain. These findings are in sharp contrast to the protective potential of ROS against other fungal pathogens, and highlight the pivotal role that ROS can fulfill in shaping the profile of the host’s immune response.

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Section: Discussionmentioning

confidence: 99%

In the Absence of Reactive Oxygen Species, T Cells Default to a Th1 Phenotype and Mediate Protection against Pulmonary Cryptococcus neoformans Infection

Snelgrove

Edwards

Williams

et al. 2006

The Journal of Immunology

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“…C. neoformans B-3501 (ATCC 34873; American Type Culture Collection, Manassas, VA) is a serotype D strain that was chosen because it is the parent strain for the acapsular mutant Cap 67 (ATCC 52817) (26), which has been shown to be complemented to the encapsulated strain by a single gene (27). Serotype D strains are pathogenic and are common clinical isolates in Europe (28 -30).…”

Section: Culture Of C Neoformansmentioning

confidence: 99%

“…The cryptococcal capsule is composed predominantly (80 -90%) of glucuronoxylomannan (GXM), and several acapsular mutants lack the ability to produce this polysaccharide (26). To determine whether capsular GXM is required for modulation of chemokine production, C. neoformans strain B-3501 was compared with its acapsular variant, Cap 67.…”

Section: Inhibition Of Ec Chemokine Production Is Independent Of Fungmentioning

confidence: 99%

Inhibition of Human Endothelial Cell Chemokine Production by the Opportunistic Fungal PathogenCryptococcus neoformans

Mozaffarian

Casadevall

Berman

2000

The Journal of Immunology

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Cryptococcus neoformans is an encapsulated fungal pathogen commonly acquired by inhalation. Extrapulmonary dissemination can lead to infection of the bloodstream and various organs, most commonly resulting in meningoencephalitis. However, infection with C. neoformans is often characterized by a scant inflammatory response. The leukocyte response to infection depends in part upon a gradient of chemotactic factors and adhesion molecules expressed by the host vascular endothelium, yet the inflammatory response of human endothelial cells (EC) to C. neoformans has not been previously investigated. We found that incubation of primary human EC with C. neoformans did not induce chemokine synthesis, and resulted in differential inhibition of cytokine-induced IL-8, IFN-γ-inducible protein-10, and monocyte chemoattractant protein-1. In contrast, C. neoformans had little effect on EC surface expression of the leukocyte ligand, ICAM-1, as determined by flow cytometry. Modulation of chemokine production was dependent on the chemokine under study, the inoculum of C. neoformans used, fungal viability, and cell-cell contact, but independent of cryptococcal strain or encapsulation. These observations suggest a novel mechanism whereby C. neoformans can affect EC function and interfere with the host inflammatory response.

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“…For example, production of the pigment melanin is important for virulence and is thought to protect the organism from toxic oxygen radicals produced by host phagocytes (Kozel, 1995), while production of the metalloenzyme urease, which catalyses the hydrolysis of urea to ammonia and carbamate, may function by altering host immune function (Cox et al, 2000). A prominent structure associated with virulence is the polysaccharide capsule, which inhibits phagocytosis by host monocytes or macrophages (Fromtling et al, 1982;Kozel & Cazin, 1971;Chang & Kwon-Chung, 1994). …”

Section: Introductionmentioning

confidence: 99%

The Ess1 prolyl isomerase is dispensable for growth but required for virulence in Cryptococcus neoformans

et al. 2005

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Cryptococcus neoformans is an important human fungal pathogen that also serves as a model for studies of fungal pathogenesis. C. neoformans contains several genes encoding peptidyl-prolyl cis/trans isomerases (PPIases), enzymes that catalyse changes in the folding and conformation of target proteins. Three distinct classes of PPIases have been identified: cyclophilins, FK506-binding proteins (FKBPs) and parvulins. This paper reports the cloning and characterization of ESS1, which is believed to be the first (and probably only) parvulin-class PPIase in C. neoformans. It is shown that ESS1 from C. neoformans is structurally and functionally homologous to ESS1 from Saccharomyces cerevisiae, which encodes an essential PPIase that interacts with RNA polymerase II and plays a role in transcription. In C. neoformans, ESS1 was found to be dispensable for growth, haploid fruiting and capsule formation. However, ESS1 was required for virulence in a murine model of cryptococcosis. Loss of virulence might have been due to the defects in melanin and urease production observed in ess1 mutants, or to defects in transcription of as-yet-unidentified virulence genes. The fact that Ess1 is not essential in C. neoformans suggests that, in this organism, some of its functions might be subsumed by other prolyl isomerases, in particular, cyclophilins Cpa1 or Cpa2. This is supported by the finding that ess1 mutants were hypersensitive to cyclosporin A. C. neoformans might therefore be a useful organism in which to investigate crosstalk among different families of prolyl isomerases.

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Decreased virulence in stable, acapsular mutants ofCryptococcus neoformans

Cited by 184 publications

References 12 publications

In the Absence of Reactive Oxygen Species, T Cells Default to a Th1 Phenotype and Mediate Protection against Pulmonary Cryptococcus neoformans Infection

In the Absence of Reactive Oxygen Species, T Cells Default to a Th1 Phenotype and Mediate Protection against Pulmonary Cryptococcus neoformans Infection

Inhibition of Human Endothelial Cell Chemokine Production by the Opportunistic Fungal PathogenCryptococcus neoformans

The Ess1 prolyl isomerase is dispensable for growth but required for virulence in Cryptococcus neoformans

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