Metabolic adaptation in Cryptococcus neoformans during early murine pulmonary infection

Mol Microbiol. 2008 Sep;69(6):1456-75. doi: 10.1111/j.1365-2958.2008.06374.x. Epub 2008 Jul 30.

Abstract

The pathogenic fungus Cryptococcus neoformans generally initiates infection in mammalian lung tissue and subsequently disseminates to the brain. We performed serial analysis of gene expression (SAGE) on C. neoformans cells recovered from the lungs of mice and found elevated expression of genes for central carbon metabolism including functions for acetyl-CoA production and utilization. Deletion of the highly expressed ACS1 gene encoding acetyl-CoA synthetase revealed a requirement for growth on acetate and for full virulence. Transcripts for transporters (e.g. for monosaccharides, iron, copper and acetate) and for stress-response proteins were also elevated thus indicating a nutrient-limited and hostile host environment. The pattern of regulation was reminiscent of the control of alternative carbon source utilization and stress response by the Snf1 protein kinase in Saccharomyces cerevisiae. A snf1 mutant of C. neoformans showed defects in alternative carbon source utilization, the response to nitrosative stress, melanin production and virulence. However, loss of Snf1 did not influence the expression of a set of genes for carbon metabolism that were elevated upon lung infection. Taken together, the results reveal specific metabolic adaptations of C. neoformans during pulmonary infection and indicate a role for ACS1 and SNF1 in virulence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetic Acid / metabolism
  • Adaptation, Physiological*
  • Animals
  • Carbon / metabolism
  • Coenzyme A Ligases / genetics
  • Coenzyme A Ligases / metabolism
  • Cryptococcosis / microbiology*
  • Cryptococcus neoformans / metabolism*
  • Cryptococcus neoformans / physiology*
  • Female
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation, Fungal*
  • Lung / microbiology
  • Mice
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Virulence
  • Virulence Factors / genetics
  • Virulence Factors / metabolism

Substances

  • Virulence Factors
  • Carbon
  • SNF1-related protein kinases
  • Protein-Serine-Threonine Kinases
  • Coenzyme A Ligases
  • Acsl1 protein, rat
  • Acetic Acid