Host lipidome analysis during rhinovirus replication in HBECs identifies potential therapeutic targets
Host lipidome analysis during rhinovirus replication in HBECs identifies potential therapeutic targets
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DOI：
10.1194/jlr.m085910
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发表时间：
2018-09-01
影响因子：
6.5
通讯作者：
Wakelam, Michael J. O.
中科院分区：
文献类型：
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作者：
An Nguyen;Guedan, Anabel;Wakelam, Michael J. O.
在哮喘或慢性阻塞性肺病患者中，鼻病毒（RV）感染可引起疾病急性恶化，治疗选择有限。病毒在宿主细胞中的复制诱导细胞内膜的显著重塑，但很少有研究探讨这一机制或作为治疗机会。我们进行了公正的lipidomic分析人支气管上皮细胞感染超过6小时的时间与RV的RV-A1 b株，以确定493个不同的脂质种类的变化。通过途径和网络分析，我们确定了一些脂质代谢和信号传导酶的表观活性的时间变化。特别是，分析强调FA合成和神经酰胺代谢作为潜在的抗鼻病毒靶点。为了验证这些酶在病毒复制中的重要性，我们探索了市售酶抑制剂对RV-A1 b感染和复制的影响。Ceranib-1、D 609和C75是最有效的抑制剂，这证实FAS和神经酰胺酶是鼻病毒感染的潜在抑制靶点。更广泛地说，这项研究证明了脂质组学和途径分析在确定治疗人类疾病的新靶点方面的潜力。
In patients with asthma or chronic obstructive pulmonary disease, rhinovirus (RV) infections can provoke acute worsening of disease, and limited treatment options exist. Viral replication in the host cell induces significant remodeling of intracellular membranes, but few studies have explored this mechanistically or as a therapeutic opportunity. We performed unbiased lipidomic analysis on human bronchial epithelial cells infected over a 6 h period with the RV-A1b strain of RV to determine changes in 493 distinct lipid species. Through pathway and network analysis, we identified temporal changes in the apparent activities of a number of lipid metabolizing and signaling enzymes. In particular, analysis highlighted FA synthesis and ceramide metabolism as potential anti-rhinoviral targets. To validate the importance of these enzymes in viral replication, we explored the effects of commercially available enzyme inhibitors upon RV-A1b infection and replication. Ceranib-1, D609, and C75 were the most potent inhibitors, which confirmed that FAS and ceramidase are potential inhibitory targets in rhinoviral infections. More broadly, this study demonstrates the potential of lipidomics and pathway analysis to identify novel targets to treat human disorders.