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

Cryptococcus neoformans is a leading cause of life-threatening fungal infec tion in immunocompromised patients. Inositol-phosphoryl ceramide synthase 1 (Ipc1) is a fungus-specific enzyme, encoded by the essential IPC1 gene, th at catalyzes the formation of complex sphingolipids and may also regulate t he levels of phytoceramide and diacylglycerol. Here, we investigated the fu nctions of this essential gene by modulating its expression in C. neoforman s using a galactose-inducible promoter. Down-regulation of IPC1 significant ly lowers the expression of certain virulence traits such as melanin pigmen tation and, remarkably, impairs pathogenicity of C. neoformans in an establ ished rabbit model. Interestingly, we found that IPC1 down-regulation signi ficantly decreases the intracellular growth of C. neoformans in the J774.16 murine macrophage-like cells. Finally, we studied the effect of IPC1 expre ssion under different stress conditions and found that down-regulation of I PC1 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 f irst to define a novel and crucial function of Ipc1 in fungal pathogenesis.