title: 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). In this article, we report that lipoprotein deficiency impairs early pulmonary innate defense against S. aureus quorum-sensing-dependent pathogenesis. Specifically, apolipoprotein B levels in the lung early postinfection 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 posttrauma pneumonia susceptibility to both Gram-positive and -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.
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131; and.
authors.forename: Brett C
authors.initials: BC
authors.lastname: Manifold-Wheeler
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131; and.
authors.forename: Bradley O
authors.initials: BO
authors.lastname: Elmore
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131; and.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Triplett
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131; and.
authors.forename: Moriah J
authors.initials: MJ
authors.lastname: Castleman
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0002-2222-4115
authors.initials: M
authors.lastname: Otto
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131; and phall@salud.unm.edu.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Hall
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D007009:Hypolipoproteinemias / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology; D008077:Lipoproteins, LDL / Q000097:blood* / Q000276:immunology; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011023:Pneumonia, Staphylococcal / Q000276:immunology*; D053038:Quorum Sensing / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics; D013211:Staphylococcus aureus / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: C095698:Agr protein, Staphylococcus aureus; D001055:Apolipoproteins B; D001426:Bacterial Proteins; D008077:Lipoproteins, LDL; D015534:Trans-Activators