Sphingomyelin synthase 2 regulates host protection conferred by the administration of Cryptococcus neoformans Δsgl1 strain.

Sphingolipids are fundamental components of the plasma membrane that regulate immune receptor organization and host responses to infection. Here, we identify sphingomyelin synthase 2 (SMS2) as a critical mediator of antifungal host defense against Cryptococcus neoformans. SMS2 deficiency reduces sphingomyelin and increases ceramide levels, altering membrane lipid composition and impairing receptor localization. This is associated with decreased plasma membrane toll-like receptor 2, attenuated signaling, and reduced IL-17A and IFNγ production by γδ T cells. Macrophages lacking SMS2 exhibit impaired phagocytosis, resulting in inefficient clearance of the attenuated C. neoformans Δsgl1 strain. Consequently, SMS2-deficient mice fail to develop effective vaccine-induced protection and show increased susceptibility to secondary infection with WT C. neoformans. Mechanistically, bSMase-driven alterations in SM/ceramide balance are associated with disruption of membrane organization and reduced toll-like receptor 2 and cholera toxin B staining, suggesting that SMS2-dependent sphingomyelin regulation represents a key mechanism linking membrane lipid composition to innate immune signaling, phagocytosis, and antifungal host defense against C. neoformans.