Marmoset Viral Hepatic Inflammation Induced by Hepatitis C Virus Core Protein via IL-32

Bochao Liu,Qi Wang,Jean-Pierre Allain,Chengyao Li,Yongshui Fu,Shengxue Luo,Wenjing Wang,Ling Zhang,Xiaorui Ma,Tingting Li

doi:10.3389/fcimb.2020.00135

Abstract

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.

Highlights

Hepatitis C virus (HCV), a serious infectious disease that is transmitted through blood, is one of the most common viral causes of liver disease, affecting more than 170 million people worldwide
A study suggested that expression of the core protein increased cell proliferation, DNA synthesis, apoptosis, cell cycle progression, cell transformation, steatosis, and hepatocellular carcinoma (HCC) in transgenic mice (Moriya et al, 1998)
Looking back at our previously reported study (Li et al, 2014), we observed that the marmosets infected with HCV core protein-containing viral chimera experienced more severe hepatic inflammation than animals infected with viral chimera that did not express HCV core protein

Summary

Introduction

Hepatitis C virus (HCV), a serious infectious disease that is transmitted through blood, is one of the most common viral causes of liver disease, affecting more than 170 million people worldwide. HCV is a single-stranded RNA flavivirus and has a 9.6-kilobase genome (kb) that encodes 10 proteins: structural core and envelope E1, E2, and p7, non-structural NS2, NS3, NS4A, NS4B, NS5A, and NS5B, respectively. Some of these proteins could interact with host cellular factors and promote tumor growth in vivo and in vitro (Ray et al, 1996; Gale et al, 1999; Park et al, 2000; Lerat et al, 2002). HCV core protein is involved in the regulation of liver cell proliferation and cell transformation. In order to explore the core protein function, the marmosets infected with chimeric viruses of HCV structural core and envelope protein (CE1E2p7) or envelope protein (E1E2p7) sequences integrated within GBV-B genome were comparatively analyzed in combination with previous infected animals (Li et al, 2014)

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Results

Conclusion