Serum Lipoproteins Are Critical for Pulmonary Innate Defense against Staphylococcus aureus Quorum Sensing

Abstract

Hyperlipidemia has been extensively studied in the context of atherosclerosis, whereas the potential health consequences of the opposite extreme, hypolipidemia, remain largely uninvestigated. Circulating lipoproteins are essential carriers of insoluble lipid molecules and are increasingly recognized as innate immune effectors. Importantly, severe hypolipidemia, which may occur with trauma or critical illness, is clinically associated with bacterial pneumonia. To test the hypothesis that circulating lipoproteins are essential for optimal host innate defense in the lung, we used lipoprotein deficient mice and a mouse model of Staphylococcus aureus pneumonia in which invasive infection requires virulence factor expression controlled by the accessory gene regulator (agr) operon. Activation of agr and subsequent virulence factor expression is inhibited by apolipoprotein B, the structural protein of low density lipoprotein, which binds and sequesters the secreted agr-signaling peptide (AIP). Here we report that lipoprotein deficiency impairs early pulmonary innate defense against S. aureus quorum-sensing dependent pathogenesis. Specifically, apoB levels in the lung early post-infection are significantly reduced with lipoprotein deficiency, coinciding with impaired host control of S. aureus agr-signaling and increased agr-dependent morbidity (weight loss) and inflammation. Given that lipoproteins also inhibit LTA- and LPS-mediated inflammation, these results suggest that hypolipidemia may broadly impact post-trauma pneumonia susceptibility to both Gram positive and Gram negative pathogens. Together with previous reports demonstrating that hyperlipidemia also impairs lung innate defense, these results suggest that maintenance of normal serum lipoprotein levels is necessary for optimal host innate defense in the lung.

Staphylococcus aureus Utilizes Host-Derived Lipoprotein Particles as Sources of Fatty Acids

“…Consistent with this, spontaneous triclosan-resistant fatty acid auxotrophs have previously been isolated from clinical samples (24). Previous studies focused on the interactions between S. aureus and lipoprotein particles showed that LDLs defended against S. aureus infection by sequestering autoinducing peptide and phenol-soluble modulins (40)(41)(42)(43)70). Our studies expand on these findings by demonstrating that S. aureus is also capable of utilizing LDLs as a source of fatty acids.…”

“…Notably, expression of secreted lipases is a clinically defining feature of S. aureus, and most strains encode multiple lipases (37,38). Previous studies established that LDL particles bind to and sequester factors secreted by S. aureus, such as autoinducing peptides and alpha-toxin (39)(40)(41)(42)(43), but the capacity of LDLs to serve as an exogenous source of fatty acids for S. aureus has not been explored.…”

Impact of Environmental Cues on Staphylococcal Quorum Sensing and Biofilm Development

“…Consistent with the generality of this mechanism, it was recently reported that apolipoprotein B100 in VLDL and apoB48 in chylomicrons also inhibit quorum sensing by AIP sequestration (37). Most recently, it was found that mice with hypolipidemia that reduced ApoB levels in their lungs suffered from increased morbidity and inflammation in an S. aureus pneumonia model (38), highlighting the importance of sequestration of AIP by serum lipoproteins as a mechanism of innate immunity. In a separate study, James et al (34) discovered that AgrC point mutations that render AgrC constitutively active overcame quorum-sensing inhibition by serum lipoproteins, leading them to conclude that "sequestration of the AIP is likely to be the only mechanism by which the host innate immune response limits agr expression at the transcriptional level."…”

Host-inherent variability influences the transcriptional response of Staphylococcus aureus during in vivo infection

“…5c ). Furthermore, ApoB has been shown to contribute to the host defense against S. aureus in experimental models of skin 42 and respiratory 43 infection by antagonizing the agr quorum sensing system of S. aureus . To validate this hypothesis, A/J and C57BL/6 mice were treated with 4-aminopyrazolopyrimidine (4-APP), a drug that impairs low-density lipoprotein secretion 44 , and subsequently infected intravenously with S. aureus.…”