Manifold-Wheeler Brett C, Elmore Bradley O, Triplett Kathleen D, Castleman Moriah J, Otto Michael, Hall Pamela R
Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131; and.
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 2016 Jan 1;196(1):328-35. doi: 10.4049/jimmunol.1501835. Epub 2015 Nov 25.
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.
高脂血症已在动脉粥样硬化的背景下得到广泛研究，而另一个极端情况——低脂血症的潜在健康后果在很大程度上仍未得到充分研究。循环脂蛋白是不溶性脂质分子的重要载体，并且越来越被认为是先天性免疫效应器。重要的是，严重低脂血症可能发生于创伤或危重病时，在临床上与细菌性肺炎相关。为了验证循环脂蛋白对肺部最佳宿主先天性防御至关重要这一假说，我们使用了脂蛋白缺陷小鼠以及金黄色葡萄球菌肺炎小鼠模型，其中侵袭性感染需要由辅助基因调节子（agr）操纵子控制的毒力因子表达。载脂蛋白B（低密度脂蛋白的结构蛋白）可结合并隔离分泌的agr信号肽（AIP），从而抑制agr的激活及随后的毒力因子表达。在本文中，我们报告脂蛋白缺乏会损害对金黄色葡萄球菌群体感应依赖性发病机制的早期肺部先天性防御。具体而言，脂蛋白缺乏会导致感染后早期肺内载脂蛋白B水平显著降低，这与宿主对金黄色葡萄球菌agr信号的控制受损以及agr依赖性发病率（体重减轻）和炎症增加相一致。鉴于脂蛋白还能抑制脂磷壁酸和脂多糖介导的炎症，这些结果表明低脂血症可能广泛影响创伤后肺炎对革兰氏阳性和阴性病原体的易感性。与先前表明高脂血症也会损害肺部先天性防御的报告一起，这些结果表明维持正常血清脂蛋白水平对于肺部最佳宿主先天性防御是必要的。
