Hypothetical model of VitD3 effects in D 3 -MDMs during DENV-2 infection.

(A) VitD3 can be found as inactive form 25(OH) 2 D2 (calcidiol), as active form 1,25(OH) 2 D3 (calcitriol), or be converted from inactive to active form within the cell by the action of CYP7B1. VitD3 interacts with the vitamin D receptor (VDR) present in the nuclei and associates then, with the nuclear receptor retinoid X receptor (RXR). Together, they act as transcription factors that will increase the expression of genes that have vitamin D response elements (VDRE) [ 58 , 59 ]. Genomic effects of VitD3 during DENV-2 infection include decreased expression of IL-6, TNF-α, RIG-I, TLR3, TLR7 and decreased production of reactive oxygen species (ROS). Since ROS can induce mitochondrial damage and then increase activation and expression of TLR9 [ 28 ], VitD3 reduced TLR9 expression indirectly. (B) As a non-genomic effect, VitD3 can bind to VDR that is initially bound to STAT1 [ 29 ], and indirectly enhance the activity of the JAK-STAT signaling pathway and IFN-I activity, thus increasing expression of PKR and OAS1.