Lipolysis of host triacylglyceride-rich lipoproteins creates a toxic microenvironment for <i>Staphylococcus aureus</i>

<i>Staphylococcus aureus</i> secretes lipases that hydrolyze glycerol esters to mitigate host detection and scavenge fatty acids for membrane synthesis, but exposure to host-derived polyunsaturated fatty acids (PUFA) can be toxic. Here, we show that host hyperlipidemia protects against <i>S. aureus</i> osteomyelitis by engaging this vulnerability. Using a mouse model of severe hyperlipidemia, we show that PUFA-enriched plasma triacylglycerides are associated with reduced bacterial burden and bone destruction from injury-associated osteomyelitis. <i>In vitro</i> , human triacylglyceride-rich lipoproteins (TRL) exhibit potent bactericidal activity against post-exponential <i>S. aureus</i> that requires lipase activity of glycerol ester hydrolase ( <i>geh</i> ). Pre-exponential exposure to TRL suppressed <i>agr</i> quorum-sensing, blunting <i>geh</i> expression and toxicity; however, bactericidal activity of TRL could be restored by exogenous lipoprotein lipase. Together, these findings reveal TRL as active antimicrobial particles whose toxicity is unmasked by lipolysis and suggest that modulation of host lipid metabolism may provide new therapeutic opportunities for chronic <i>S. aureus</i> infection.