PROJECT SUMMARY This proposal aims to determine whether LXRα phosphorylation at serine 196 (S196) is a possible target for therapeutic intervention in MRSA. Our previous published studies demonstrated in cultured cells and mouse models of cardiometabolic diseases that the non-phosphorylated form of LXRα S196A reprograms the LXR- modulated transcriptome and produces a more robust anti-inflammatory response. We hypothesize that reducing LXRα phosphorylation in myeloid and endothelial cells would reduce MRSA pathology via resistance to MRSA toxin-mediated killing via enhanced exosome release. To test this, we will develop a mouse model that harbors either myeloid or endothelial cell-specific LXRα S196A knock-in mice and compare the mortality and exosome abundance in the blood upon MRSA infection to that of WT LXRα mice and global LXRα S196A mice. We will also generate primary macrophages and endothelial cells from wild-type and LXRα S196A mice and measure effects on gene expression upon infection with MRSA to reveal genes and pathways modulated by LXRα S196 phosphorylation that can be manipulated for preventive and therapeutic purposes. We will also test whether pharmacological interventions that promote the non- phosphorylated form of the wild-type LXRα can protect wild-type mice and human PBMCs from lethal MRSA infection. Successful completion of the aims will determine whether LXRα phosphorylation represents a tractable target for treating MRSA due to its ability to reduce inflammatory gene expression.