Abstract
Serum lipoproteins (LP) are increasingly being recognized as dual purpose molecules that contribute to both cholesterol homeostasis and host innate defense. In fact, very low LP levels are associated with increased risk of bacterial infection in critically ill patients. In this respect, we reported that apolipoprotein B100 (apoB100), the 4536 amino acid structural protein of very low density lipoprotein (VLDL) produced by the liver, limits Staphylococcus aureus pathogenesis. S. aureus uses quorum-sensing (QS) via the accessory gene regulator (agr) operon and an autoinducing peptide (AIP) to coordinate expression of over 200 virulence genes. ApoB100 prevents agr activation by binding and sequestering secreted AIP. Importantly, human serum LP are produced not only by the liver, but are also produced by enterocytes, in the form of chylomicrons, during uptake of dietary lipids. In contrast to apoB100 in VLDL, human enterocytes use apoB48, the N-terminal 2152 amino acids (48%) of apoB100, as the structural component of chylomicrons. Interestingly, enteral feeding of critically ill patients has been associated with decreased risk of infectious complications, suggesting chylomicrons could contribute to host innate defense in critically ill patients when serum LP production by the liver is limited during the acute phase response. Therefore, we hypothesized that apoB48 would be sufficient to antagonize S. aureus QS. As expected, isolated apoB48-LP bound immobilized AIP and antagonized agr-signaling. ApoB48- and apoB100-LP inhibited agr activation with IC50s of 3.5 and 2.3 nM, respectively, demonstrating a conserved AIP binding site. Importantly, apoB48-LP antagonized QS, limited morbidity and promoted bacterial clearance in a mouse model of S. aureus infection. This work demonstrates that both naturally occurring forms of apolipoprotein B can antagonize S. aureus QS, and may suggest a previously unrecognized role for chylomicrons and enterocytes in host innate defense against S. aureus QS-mediated pathogenesis.
Highlights
Serum lipoproteins have historically had two primary functions: 1) to transport cholesterol and other insoluble lipids from their source to peripheral tissues to be used for cell membrane assembly, steroid production and fuel, and 2) to transport excess cholesterol from the tissues to the liver for clearance
Lipoproteins containing apolipoprotein B100 (apoB100) are largely cleared by the LDL receptor (LDLR) which binds to the LDLR-binding sequence in the C-terminus of apoB100 (Fig 1)
Clearance of apoB48 is mediated by apoE, an exchangeable apolipoprotein which facilitates uptake of chylomicron remnants via the LDLR and low-density lipoprotein related protein (LRP) [29,30,31]
Summary
Serum lipoproteins have historically had two primary functions: 1) to transport cholesterol and other insoluble lipids from their source to peripheral tissues to be used for cell membrane assembly, steroid production and fuel (termed forward cholesterol transport), and 2) to transport excess cholesterol from the tissues to the liver for clearance (reviewed in [1]). Some studies have shown that enteral feeding of critically ill patients, which preserves the contribution of the gut to nutritional processing, is associated with reduced risk of infectious complications compared to parenteral (intravenous) feeding [8, 9]. This suggests that, beyond their role in lipid transport, chylomicrons produced by enterocytes may contribute to limiting the pathogenesis of bacterial infection. VLDL, LDL (produced by lipase reduction of VLDL), HDL and their components are being increasingly recognized as host innate effectors, much less is known about the contribution of chylomicrons and their components to protection against bacterial pathogenesis
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