Cryptococcus neoformans (Cn) is a deadly fungal pathogen whose intracellular lifestyle is important for virulence. Host mechanisms controlling fungal phagocytosis and replication remain obscure. Here, we describe insights that have emerged from a global phosphoproteomic analysis of the host response to Cryptococcus infection. Our analysis revealed diverse host proteins that were differentially phosphorylated following fungal infection, indicating global reprogramming of host kinase signaling during this process. Notably, phagocytosis of the pathogen activated the host autophagy initiation complex (AIC) as well as regulatory components that reside upstream of this complex. Cn-containing vacuoles (CnCVs) were found to be decorated with the cell surface marker CD44, which colocalized with components of the AIC complex. Taken together, these findings suggest that associations between CD44 and AIC proteins confer susceptibility to infection, thereby implicating novel host mechanisms in regulating fungal intracellular parasitism.