Roles for Inositol-phosphoryl ceramide synthase 1 (IPC1) in pathogenesis of C. neoformans

Chiara Luberto, Dena L. Toffaletti, Elizabeth A. Wills, Stephanie C. Tucker, Arturo Casadevall, John R. Perfect, Yusuf A. Hannun, Maurizio Del Poeta

Research output: Contribution to journalArticlepeer-review

Abstract

Cryptococcus neoformans is a leading cause of life-threatening fungal infection in immunocompromised patients. Inositol-phosphoryl ceramide synthase 1 (Ipc1) is a fungus-specific enzyme, encoded by the essential IPC1 gene, that catalyzes the formation of complex sphingolipids and may also regulate the levels of phytoceramide and diacylglycerol. Here, we investigated the functions of this essential gene by modulating its expression in C. neoformans using a galactose-inducible promoter. Down-regulation of IPC1 significantly lowers the expression of certain virulence traits such as melanin pigmentation and, remarkably, impairs pathogenicity of C. neoformans in an established rabbit model. Interestingly, we found that IPC1 down-regulation significantly decreases the intracellular growth of C. neoformans in the J774.16 murine macrophage-like cells. Finally, we studied the effect of IPC1 expression under different stress conditions and found that down-regulation of IPC1 confers a defect on in vitro growth at low pH. Because this environment is similar to that in the phagolysosome of J774.16 macrophage-like cells, our findings indicate that down-regulation of IPC1 confers a growth defect in vivo through a pH-dependent mechanism. In conclusion, our study is the first to define a novel and crucial function of Ipc1 in fungal pathogenesis.

Original languageEnglish (US)
Pages (from-to)201-212
Number of pages12
JournalGenes and Development
Volume15
Issue number2
DOIs
StatePublished - Jan 15 2001
Externally publishedYes

Keywords

  • Cryptococcus neoformans
  • Sphingolipids
  • Virulence

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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