Transcriptome profiles of primary human hepatocytes treated with HBV preS1 peptide with or without bile acids

Chronic hepatitis B, C and D virus (HBV, HCV, HDV) infections are leading causes of liver disease and cancer worldwide. Although these viruses differ markedly in their life cycle and genomic organization, they exclusively infect hepatocytes. Recently, the sodium taurocholate cotransporting polypeptide (NTCP) was identified as the first functional receptor for HBV and HDV. Here, we report that NTCP also facilitates HCV entry into human hepatocytes, by augmenting the bile acids-mediated repression of IFN-stimulated genes (ISGs), including IFITM2 and IFITM3, to increase the susceptibility of cells to HCV entry. Furthermore, an HBV-derived preS1 peptide, known to bind NTCP and to inhibit bile acids uptake and HBV infection, inhibits HCV entry by enhancing the expression of ISGs. Our study highlights NTCP as a novel player linking bile acids metabolism to the interferon response in hepatocytes and establishes a role for NTCP in the entry process of multiple hepatotropic viruses, via distinct mechanisms. Collectively, these findings enhance our understanding of hepatitis virus-host interactions and suggest NTCP as an attractive antiviral target for HBV/HCV co-infection. Transcriptome profiling by DNA microarray of primary human hepatocytes.

慢性乙型肝炎病毒（HBV）、丙型肝炎病毒（HCV）与丁型肝炎病毒（HDV）感染是全球范围内导致肝脏疾病及肝癌的主要病因。尽管这三类病毒在生命周期与基因组结构上存在显著差异，但它们均仅感染肝细胞。近期，牛磺胆酸钠协同转运多肽（sodium taurocholate cotransporting polypeptide, NTCP）被鉴定为HBV与HDV的首个功能性受体。本研究证实，NTCP亦可促进HCV入侵人肝细胞：其通过增强胆汁酸介导的干扰素刺激基因（IFN-stimulated genes, ISGs，包含IFITM2与IFITM3）的转录抑制，提升细胞对HCV入侵的易感性。此外，已知可结合NTCP、抑制胆汁酸摄取与HBV感染的HBV来源前S1肽段，可通过上调ISGs的表达阻断HCV入侵。本研究揭示，NTCP是连接肝细胞内胆汁酸代谢与干扰素应答的全新调控因子，并证实NTCP可通过不同机制参与多种嗜肝病毒的入侵过程。综上，本研究结果加深了我们对肝炎病毒-宿主相互作用的认知，并提示NTCP可作为HBV/HCV合并感染的潜在抗病毒治疗靶点。本研究通过DNA微阵列技术完成了原代人肝细胞的转录组分析。