HECT E3 Ubiquitin ligase Nedd4 is required for anti-fungal innate immune response

Candida albicans is the most common cause of fungal infections in humans, and disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with 45% to 75% mortality rate. The understanding of the host–pathogen interactions and the mechanisms of immune regulation against fungal spread is critical for developing immune-based strategies to combat candidemia. Nedd4 (neuronal precursor cell-expressed developmentally down-regulated 4) is a HECT-type E3 ubiquitin ligase which has been shown to positively regulate T cell activation and proliferation. However, the role of Nedd4 in innate immunity is completely unknown. To elucidate the role of Nedd4 in innate immune response against fungal infection, we generated the mice bearing LoxP -flanked alleles encoding Nedd4 with Rosa26-Cre-ER T2 mice to generate Nedd4 fl/fl Rosa26-Cre-ER T2 mice (called ‘ Nedd4 CreER mice ’ here). We also generated mice deficient for Nedd4 in dendritic cells (DC) ( Cd11c Cre.Nedd4 f/f ) or macrophages ( LysM Cre.Nedd4 f/f ). We found that although Nedd4 might not regulate the signaling via TLRs and Dectin-1, Rosa26-Cre-ER T2 mice treated with tamoxifen or mice deficient for Nedd4 in the myeloid cell lineages (macrophages and dendritic cells) are highly susceptible to systemic C. albicans infection, which correlates with defective pro-inflammatory cytokines in the sera, impaired leukocyte recruitment to the kidneys, defective ROS expression by the granulocytes in the kidneys, and heightened kidney fungal burden. Therefore, our data suggest that Nedd4 expression in the myeloid cells is crucial for C-type lectin receptor (CLR)-mediated innate immune response against systemic C. albicans infection.