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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.

Roles for inositol-phosphoryl ceramide synthase 1 (IPC1) in pathogenesis ofC. neoformans