Reduced DMPC and PMPC in lung surfactant promote SARS-CoV-2 infection in obesity.
Reduced DMPC and PMPC in lung surfactant promote SARS-CoV-2 infection in obesity.
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DOI：
10.1016/j.metabol.2022.155181
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发表时间：
2022-06
期刊：
影响因子：
--
通讯作者：
Yang Q
中科院分区：
文献类型：
--
作者：
Du K;Sun L;Luo Z;Cao Y;Sun Q;Zhang K;Faizy A;Piomelli D;Lu X;Shan J;Yang Q
肥胖是导致 SARS-CoV-2 病毒载量升高、需要住院治疗的严重 COVID-19 肺炎以及预后较差的既定危险因素。然而，风险增加的根本机制尚不清楚。 SARS-CoV-2 是一种呼吸道病毒，主要进入肺部的途径是 SARS-CoV-2 的刺突蛋白与肺细胞上的 ACE2 受体结合。 II 型肺细胞产生的肺表面活性物质在呼吸道防御感染中发挥着重要作用。表面活性剂主要含有脂质，尤其是磷脂酰胆碱（PC），而肥胖的特点是脂质代谢异常。我们假设肥胖者肺表面活性剂脂质成分的改变可能会促进 SARS-CoV-2 感染，从而导致严重的 COVID-19 疾病。使用 LC-MS/MS 对肺组织和支气管肺泡灌洗液 (BALF) 进行脂质组学分析。在 ACE2 过表达的 HEK293T 细胞和内源性 ACE2 表达的 Vero-E6 细胞中研究了 PC 对 SARS-CoV-2 假病毒感染的影响。对于细胞-细胞融合测定，分别使用表达 SARS-CoV-2 Spike/eGFP 的 HEK293T-ACE2 和 HEK293T 作为靶细胞和效应细胞。脂质组学分析表明，高脂饮食诱导的肥胖小鼠的肺组织和 BALF 中含有肉豆蔻酸的二肉豆蔻酰 PC (DMPC) 和棕榈酰肉豆蔻酰 PC (PMPC) 减少。 DMPC 和 PMPC 显着抑制 HEK293T-ACE2 和 Vero-E6 细胞中野生型和 D614G 突变体 SARS-CoV-2 的感染。用三肉豆蔻酸（肉豆蔻酸的甘油三酯）喂养肥胖小鼠，会增加肺表面活性物质中的 DMPC 和 PMPC 水平。经过三肉豆蔻精治疗的肥胖小鼠 BALF 中的脂质提取物可减轻野生型和 D614G 突变体 SARS-CoV-2 感染的升高。 DMPC 和 PMPC 对 SARS-CoV-2 感染的抑制作用可被胆固醇逆转。肺表面活性物质中DMPC和PMPC的减少可能会促进SARS-CoV-2感染。增加肺表面活性剂中的 DMPC 和 PMPC 可能是预防和治疗肥胖症中严重的 COVID-19 疾病的创新策略。
Obesity is an established risk factor for higher SARS-CoV-2 viral loads, severe COVID-19 pneumonia requiring hospitalization, and worse outcomes. However, the underlying mechanisms for the increased risk are not well understood. SARS-CoV-2 is a respiratory virus with the primary route of entry through the lungs, where the Spike protein of SARS-CoV-2 binds to the ACE2 receptor on pneumocytes. Lung surfactant produced by type II pneumocytes plays a major role in respiratory defense against infections. Surfactant predominantly contains lipids, especially phosphatidylcholines (PC), and obesity is characterized by aberrant lipid metabolism. We hypothesized that altered lipid composition in lung surfactant in obesity may promote SARS-CoV-2 infection, leading to severe COVID-19 disease. Lipidomic analysis of lung tissue and bronchoalveolar lavage fluid (BALF) was performed using LC-MS/MS. The effects of PCs on SARS-CoV-2 pseudovirus infection were studied in HEK293T cells with ACE2 overexpression and in Vero-E6 cells with endogenous ACE2 expression. For the cell-cell fusion assay, HEK293T-ACE2 and HEK293T expressing SARS-CoV-2 Spike/eGFP were used as the target and effector cells, respectively. Lipidomic analysis revealed that myristic acid-containing dimyristoyl-PC (DMPC) and palmitoylmyristoyl-PC (PMPC) were reduced in lung tissue and BALF from high fat diet-induced obese mice. DMPC and PMPC markedly inhibited wild type and D614G mutant SARS-CoV-2 infection in HEK293T-ACE2 and Vero-E6 cells. Feeding obese mice with trimyristin, the triglycerides of myristic acid, increased DMPC and PMPC levels in lung surfactant. Lipid extract from BALF of trimyristin-treated obese mice mitigated the elevated wild type and D614G mutant SARS-CoV-2 infection. The inhibitory effects of DMPC and PMPC on SARS-CoV-2 infection were reversed by cholesterol. The reduced DMPC and PMPC in lung surfactant may promote SARS-CoV-2 infection. Increasing DMPC and PMPC in lung surfactant could be an innovative strategy for preventing and treating severe COVID-19 disease in obesity.
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影响因子：
5.8
作者：
Li GM;Li YG;Yamate M;Li SM;Ikuta K
通讯作者：
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DOI：
10.1016/j.bbrc.2008.02.023
发表时间：
2008-05-02
影响因子：
3.1
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影响因子：
64.8
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影响因子：
7.3
作者：
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影响因子：
4.6
作者：
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通讯作者：
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