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Identification and characterization of the Cryptococcus neoformans phosphomannose isomerase-encoding gene, MAN1, and its impact on pathogenicity.

Publication ,  Journal Article
Wills, EA; Roberts, IS; Del Poeta, M; Rivera, J; Casadevall, A; Cox, GM; Perfect, JR
Published in: Mol Microbiol
May 2001

The polysaccharide capsule surrounding Cryptococcus neoformans comprises manose, xylose and glucuronic acid, of which mannose is the major constituent. The GDP-mannose biosynthesis pathway is highly conserved in fungi and consists of three key enzymes: phosphomannose isomerase (PMI), phosphomannomutase (PMM) and GDP-mannose pyrophosphorylase (GMP). The MAN1 gene, encoding for the PMI enzyme, was isolated and sequenced from C. neoformans, and a disruption of the MAN1 gene was generated. One MAN1 disruption mutant, man1, which showed poor capsule formation, reduced polysaccharide secretion and morphological abnormalities, was chosen for virulence studies. In both the rabbit and the mouse models of invasive cryptococcosis, man1 was shown to be severely impaired in its virulence, with complete elimination of the yeast from the host. A reconstituted strain of man1 was constructed using gene replacement at the native locus. The wild-type and reconstituted strains were significantly more virulent than the knock-out mutant in both animal models. Our findings reveal that PMI activity is essential for the survival of C. neoformans in the host. The fact that the man1 mutant was not pathogenic suggests that blocking mannose synthesis could be fungicidal in the mammalian host and thus an excellent target for antifungal drug development.

Duke Scholars

Published In

Mol Microbiol

DOI

ISSN

0950-382X

Publication Date

May 2001

Volume

40

Issue

3

Start / End Page

610 / 620

Location

England

Related Subject Headings

  • Virulence
  • Sequence Homology, Amino Acid
  • Rabbits
  • Mutagenesis
  • Molecular Sequence Data
  • Microbiology
  • Mice, Inbred BALB C
  • Mice
  • Mannose-6-Phosphate Isomerase
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
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Wills, E. A., Roberts, I. S., Del Poeta, M., Rivera, J., Casadevall, A., Cox, G. M., & Perfect, J. R. (2001). Identification and characterization of the Cryptococcus neoformans phosphomannose isomerase-encoding gene, MAN1, and its impact on pathogenicity. Mol Microbiol, 40(3), 610–620. https://doi.org/10.1046/j.1365-2958.2001.02401.x
Wills, E. A., I. S. Roberts, M. Del Poeta, J. Rivera, A. Casadevall, G. M. Cox, and J. R. Perfect. “Identification and characterization of the Cryptococcus neoformans phosphomannose isomerase-encoding gene, MAN1, and its impact on pathogenicity.Mol Microbiol 40, no. 3 (May 2001): 610–20. https://doi.org/10.1046/j.1365-2958.2001.02401.x.
Wills EA, Roberts IS, Del Poeta M, Rivera J, Casadevall A, Cox GM, et al. Identification and characterization of the Cryptococcus neoformans phosphomannose isomerase-encoding gene, MAN1, and its impact on pathogenicity. Mol Microbiol. 2001 May;40(3):610–20.
Wills, E. A., et al. “Identification and characterization of the Cryptococcus neoformans phosphomannose isomerase-encoding gene, MAN1, and its impact on pathogenicity.Mol Microbiol, vol. 40, no. 3, May 2001, pp. 610–20. Pubmed, doi:10.1046/j.1365-2958.2001.02401.x.
Wills EA, Roberts IS, Del Poeta M, Rivera J, Casadevall A, Cox GM, Perfect JR. Identification and characterization of the Cryptococcus neoformans phosphomannose isomerase-encoding gene, MAN1, and its impact on pathogenicity. Mol Microbiol. 2001 May;40(3):610–620.
Journal cover image

Published In

Mol Microbiol

DOI

ISSN

0950-382X

Publication Date

May 2001

Volume

40

Issue

3

Start / End Page

610 / 620

Location

England

Related Subject Headings

  • Virulence
  • Sequence Homology, Amino Acid
  • Rabbits
  • Mutagenesis
  • Molecular Sequence Data
  • Microbiology
  • Mice, Inbred BALB C
  • Mice
  • Mannose-6-Phosphate Isomerase
  • Male