基于病毒-宿主交互网络的加味芦根方治疗流行性感冒的生物信息学分析

Bioinformatics Analysis of Modified Lugen Formula in the Treatment of Influenza:Perspectives from the Virus-Host Interaction Network

目的从病毒-宿主交互界面探讨加味芦根方(芦根、全蝉蜕、僵蚕、金银花、生甘草、薄荷、羌活、葛根、柴胡)治疗流行性感冒的分子机制。方法从本草组鉴数据库收集复方的化学成分,经里宾斯基五原则筛选潜在的活性成分后,进一步在瑞士靶点预测网站预测活性成分的作用靶点;从GEO数据库挖掘人类流感芯片GSE90732的差异表达基因;从病毒-宿主相互作用搜索工具检索H1N1流感-智人蛋白交互组;整合上述生物信息集,通过Cytoscape构建蛋白质-蛋白质相互作用网络和加味芦根方-病毒-宿主交互网络,使用R软件对交集基因进行功能富集分析,最后对关键活性成分及靶点进行分子对接验证。结果获得1252个活性成分,1415个作用靶点,951个流感差异表达基因和10142对H1N1-智人蛋白互作信息。加味芦根方与流感的交集靶点有72个,功能富集显示这些靶点与宿主防御和程序性细胞死亡密切相关。交互网络拓扑分析表明,加味芦根方通过齐墩果酸、γ-十一碳酸内酯、长棘素等多种活性成分调控病毒M2、NA、NS1和HA蛋白和/或宿主HSP90AA1、NRAS和ITGB1等多个关键靶标发挥治疗作用,分子对接结果表明活性成分与靶点具有较好的结合能力。结论加味芦根方通过多种活性成分直接靶向流感病毒蛋白和/或宿主因子,从抑制病毒复制、调节宿主防御和细胞死亡等多个维度发挥抗击流感的作用。该研究为进一步实验解析加味芦根方治疗流感的分子机制提供了理论基础。

Objective To explore the therapeutic mechanism of Modified Lugen Formula(Phragmitis Rhizoma,Cicadae Periostracum,Batryticatus Bombyx,Lonicerae Japonicae Flos,Glycyrrhiza,Menthae Haplocalycis Herba,Notopterygii Rhizoma et Radix,Puerariae Lobatae Radix,Bupleuri Radix)in treating influenza from the virus-host interaction interface.Methods The phytocompounds were first collected from the HERB database,and then potential active compounds were screened out by Lipinski's rules of five.The targets of active compounds were further predicted through the SwissTargetPrediction platform.Differentially expressed genes(DEGs)were determined from the human H1N1 influenza dataset GSE90732 available in the Gene Expression Omnibus database(GEO).H1N1-Homo sapiens-related protein-protein interactions(PPIs)were gathered from the Pathogen-Host Interaction Search Tool(PHISTO).The above mentioned bioinformatic datasets were integrated.Then a PPI network and a Formula-virus-host interaction network were constructed using Cytoscape.Functional enrichment analyses were performed by using R software.Finally,molecular docking was carried out to evaluate the binding activities between the key compounds and targets.Results A total of 1252 active compounds,1415 targets,951 influenza-related DEGs,and 10142 H1N1-Homo sapiens-related PPIs were obtained.There were 72 intersection targets between the Modified Lugen Formula and influenza.Functional enrichment analyses showed that these targets are closely related to host defense and programmed cell death.The network topological analysis showed that active compounds in the Modified Lugen Formula,such as oleanolic acid,γ-undecalactone,and longispinogenin,regulate viral proteins M2,NA,NS1,and HA and/or the host factors HSP90AA1,NRAS,and ITGB1,thus exert therapeutic effect.Molecular docking results confirmed that these compounds had a good binding ability with the targets.Conclusion Multiple active ingredients in Modified Lugen Formula directly target influenza virus proteins and/or host factors,thereby play an anti-influenza role in multiple dimensions,including inhibiting virus replication,regulating host defense and cell death.This study provides a theoretical basis for further experimental analysis of the action mechanism of the Modified Lugen Formula in treating influenza.