Nitrogen source-dependent capsule induction in human pathogenic Cryptococcus species.. Cryptococcus neoformans

Cryptococcus neoformans causes meningoencephalitis and is an increasing human health threat. C. neoformans is neurotropic, and persists in the cerebrospinal fluid (CSF) of the mammalian host during infection. In order to survive in the host, pathogenic fungi must procure nutrients such as carbon and nitrogen. To enhance our understanding of nutrient acquisition during infection by Cryptococcus species, we examined utilization of nitrogen sources available in CSF. We screened for growth and capsule production of 817 global environmental and clinical isolates on various sources of nitrogen. Capsule production was assessed using ammonium and urea in the presence or absence of benomyl to determine the relationship of urea exposure to capsule production. Since urea is metabolized to ammonia and CO2 (a known signal for capsule induction), we examined urea metabolism mutants for their response to urea regarding capsule production. Non-preferred nitrogen sources were found to greatly affect capsule production in pathogenic species of Cryptococcus. Urea induced the greatest magnitude of capsule production. Capsule induction by urea was greater in Cryptococcus gattii strains than in C. neoformans strains. In addition, both environmental and clinical strains grew robustly on uric acid, casamino acids, creatinine, and asparagine as sole nitrogen sources. While substantial growth on nitrate was not apparent at day 3, growth was apparent by day 6 for all serotypes. Overall design: In this study, transcription profiles of urea pathway mutants (ure1 and amt1/2) and WT Cryptococcus neoformans strains were compared in a dye-swap experiment following 1hr exposure to proline or proline + urea (.25g/L).