Marmoset Viral Hepatic Inflammation Induced by Hepatitis C Virus Core Protein via IL-32
Marmoset Viral Hepatic Inflammation Induced by Hepatitis C Virus Core Protein via IL-32
复制标题
丙型肝炎病毒核心蛋白通过 IL-32 诱导狨猴病毒性肝脏炎症
DOI：
10.3389/fcimb.2020.00135
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发表时间：
2020-04-21
影响因子：
5.7
通讯作者：
Li, Tingting
中科院分区：
文献类型：
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作者：
Liu, Bochao;Ma, Xiaorui;Li, Tingting
含有丙型肝炎病毒（HCV）核心和包膜蛋白（E1E2p7）的GB病毒- b （GBV-B）嵌合体感染的普通狨猴比感染HCV包膜蛋白（E1E2p7）的狨猴发生更严重的肝炎，提示HCV核心蛋白可能参与了病毒性肝炎的发病机制。研究了HCV核心在肝脏炎症中的潜在作用。构建了HCV - CE1E2p7或E1E2p7嵌合感染狨猴（每组3只）肝脏组织的6个cDNA文库并进行了测序。通过差异表达基因分析，632个mRNA转录物中有30个与免疫系统过程相关，可能与肝炎有关。基于这30个差异表达基因（DEGs），通过STRING数据库构建蛋白-蛋白相互作用网络，表明IL-32可能在HCV核心相关性肝炎中发挥核心调控作用。为了研究HCV核心蛋白对IL-32产生的影响，我们将表达HCV核心蛋白和模拟构建物转染Huh7细胞。表达HCV核心蛋白的细胞IL-32 mRNA和分泌蛋白水平显著高于未表达HCV核心蛋白的细胞（P < 0.01和P < 0.001）。通过KEGG富集分析和使用特异性信号通路抑制剂LY294002抑制PI3K， IL-32的表达显著降低（P < 0.001）。综上所述，HCV核心蛋白通过PI3K途径诱导肝细胞中IL-32的表达增加，在HCV相关性重型肝炎的发生发展中发挥了重要作用。
Common marmosets infected with GB virus-B (GBV-B) chimeras containing hepatitis C virus (HCV) core and envelope proteins (CE1E2p7) developed more severe hepatitis than those infected with HCV envelope proteins (E1E2p7), suggesting that HCV core protein might be involved in the pathogenesis of viral hepatitis. The potential role of HCV core in hepatic inflammation was investigated. Six individual cDNA libraries of liver tissues from HCV CE1E2p7 or E1E2p7 chimera-infected marmosets (three animals per group) were constructed and sequenced. By differential expression gene analysis, 30 of 632 mRNA transcripts were correlated with the immune system process, which might be associated with hepatitis. A protein–protein interaction network was constituted by STRING database based on these 30 differentially expressed genes (DEGs), showing that IL-32 might play a central regulatory role in HCV core-related hepatitis. To investigate the effect of HCV core protein on IL-32 production, HCV core expressing and mock constructs were transfected into Huh7 cells. IL-32 mRNA and secretion protein were detected at significantly higher levels in cells expressing HCV core protein than in those without HCV core expression (P < 0.01 and P < 0.001, respectively). By KEGG enrichment analysis and using the specific signaling pathway inhibitor LY294002 for inhibition of PI3K, IL-32 expression was significantly reduced (P < 0.001). In conclusion, HCV core protein induces an increase of IL-32 expression via the PI3K pathway in hepatic cells, which played a major role in development of HCV-related severe hepatitis.