Serum Lipoproteins Are Critical for Pulmonary Innate Defense against Staphylococcus aureus Quorum Sensing.
Serum Lipoproteins Are Critical for Pulmonary Innate Defense against Staphylococcus aureus Quorum Sensing.
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DOI：
10.4049/jimmunol.1501835
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发表时间：
2016-01-01
期刊：
影响因子：
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通讯作者：
Hall PR
中科院分区：
文献类型：
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作者：
Manifold-Wheeler BC;Elmore BO;Triplett KD;Castleman MJ;Otto M;Hall PR
在动脉粥样硬化的背景下，高脂血症已经被广泛研究，而相反的极端，低脂血症的潜在健康后果，在很大程度上仍未被研究。循环脂蛋白是不溶性脂质分子的重要载体，越来越被认为是先天免疫效应物。重要的是，严重的低血脂，可能发生在创伤或危重疾病，在临床上与细菌性肺炎有关。为了验证循环脂蛋白对于优化宿主肺部先天防御至关重要的假设，我们使用了脂蛋白缺陷小鼠和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控子（agr）操纵子控制的毒力因子表达。载脂蛋白B是一种低密度脂蛋白的结构蛋白，可以结合并隔离分泌的agr信号肽（AIP），从而抑制agr的激活和随后的毒力因子表达。在这里，我们报告脂蛋白缺乏损害了早期肺部对金黄色葡萄球菌群体感应依赖发病机制的先天防御。具体来说，感染后早期肺部载脂蛋白ob水平随着脂蛋白缺乏而显著降低，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。鉴于脂蛋白也抑制LTA和lps介导的炎症，这些结果表明，低血脂可能广泛影响创伤后肺炎对革兰氏阳性和革兰氏阴性病原体的易感性。加上先前的报道表明高脂血症也会损害肺的先天防御，这些结果表明维持正常的血清脂蛋白水平对于肺的最佳宿主先天防御是必要的。
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.