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Survival defects of Cryptococcus neoformans mutants exposed to human cerebrospinal fluid result in attenuated virulence in an experimental model of meningitis.

Publication ,  Journal Article
Lee, A; Toffaletti, DL; Tenor, J; Soderblom, EJ; Thompson, JW; Moseley, MA; Price, M; Perfect, JR
Published in: Infect Immun
October 2010

Cryptococcus neoformans is a fungal pathogen that encounters various microenvironments during growth in the mammalian host, including intracellular vacuoles, blood, and cerebrospinal fluid (CSF). Because the CSF is isolated by the blood-brain barrier, we hypothesize that CSF presents unique stresses that C. neoformans must overcome to establish an infection. We assayed 1,201 mutants for survival defects in growth media, saline, and human CSF. We assessed CSF-specific mutants for (i) mutant survival in both human bronchoalveolar lavage (BAL) fluid and fetal bovine serum (FBS), (ii) survival in macrophages, and (iii) virulence using both Caenorhabditis elegans and rabbit models of cryptococcosis. Thirteen mutants exhibited significant survival defects unique to CSF. The mutations of three of these mutants were recreated in the clinical serotype A strain H99: deletions of the genes for a cation ATPase transporter (ena1Δ), a putative NEDD8 ubiquitin-like protein (rub1Δ), and a phosphatidylinositol 4-kinase (pik1Δ). Mutant survival rates in yeast media, saline, and BAL fluid were similar to those of the wild type; however, survival in FBS was reduced but not to the levels in CSF. These mutant strains also exhibited decreased intracellular survival in macrophages, various degrees of virulence in nematodes, and severe attenuation of survival in a rabbit meningitis model. We analyzed the CSF by mass spectrometry for candidate compounds responsible for the survival defect. Our findings indicate that the genes required for C. neoformans survival in CSF ex vivo are necessary for survival and infection in this unique host environment.

Duke Scholars

Published In

Infect Immun

DOI

EISSN

1098-5522

Publication Date

October 2010

Volume

78

Issue

10

Start / End Page

4213 / 4225

Location

United States

Related Subject Headings

  • Virulence
  • Serum
  • Rabbits
  • Osmotic Pressure
  • Mutation
  • Microbiology
  • Mice
  • Meningitis, Cryptococcal
  • Macrophages
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lee, A., Toffaletti, D. L., Tenor, J., Soderblom, E. J., Thompson, J. W., Moseley, M. A., … Perfect, J. R. (2010). Survival defects of Cryptococcus neoformans mutants exposed to human cerebrospinal fluid result in attenuated virulence in an experimental model of meningitis. Infect Immun, 78(10), 4213–4225. https://doi.org/10.1128/IAI.00551-10
Lee, Anthony, Dena L. Toffaletti, Jennifer Tenor, Erik J. Soderblom, J Will Thompson, M Arthur Moseley, Michael Price, and John R. Perfect. “Survival defects of Cryptococcus neoformans mutants exposed to human cerebrospinal fluid result in attenuated virulence in an experimental model of meningitis.Infect Immun 78, no. 10 (October 2010): 4213–25. https://doi.org/10.1128/IAI.00551-10.
Lee A, Toffaletti DL, Tenor J, Soderblom EJ, Thompson JW, Moseley MA, et al. Survival defects of Cryptococcus neoformans mutants exposed to human cerebrospinal fluid result in attenuated virulence in an experimental model of meningitis. Infect Immun. 2010 Oct;78(10):4213–25.
Lee, Anthony, et al. “Survival defects of Cryptococcus neoformans mutants exposed to human cerebrospinal fluid result in attenuated virulence in an experimental model of meningitis.Infect Immun, vol. 78, no. 10, Oct. 2010, pp. 4213–25. Pubmed, doi:10.1128/IAI.00551-10.
Lee A, Toffaletti DL, Tenor J, Soderblom EJ, Thompson JW, Moseley MA, Price M, Perfect JR. Survival defects of Cryptococcus neoformans mutants exposed to human cerebrospinal fluid result in attenuated virulence in an experimental model of meningitis. Infect Immun. 2010 Oct;78(10):4213–4225.

Published In

Infect Immun

DOI

EISSN

1098-5522

Publication Date

October 2010

Volume

78

Issue

10

Start / End Page

4213 / 4225

Location

United States

Related Subject Headings

  • Virulence
  • Serum
  • Rabbits
  • Osmotic Pressure
  • Mutation
  • Microbiology
  • Mice
  • Meningitis, Cryptococcal
  • Macrophages
  • Humans