Schupp Anna-Kathrin, Trilling Mirko, Rattay Stephanie, Le-Trilling Vu Thuy Khanh, Haselow Katrin, Stindt Jan, Zimmermann Albert, Häussinger Dieter, Hengel Hartmut, Graf Dirk
Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany.
J Virol. 2016 Jul 11;90(15):6686-6698. doi: 10.1128/JVI.00299-16. Print 2016 Aug 1.
The liver constitutes a prime site of cytomegalovirus (CMV) replication and latency. Hepatocytes produce, secrete, and recycle a chemically diverse set of bile acids, with the result that interactions between bile acids and cytomegalovirus inevitably occur. Here we determined the impact of naturally occurring bile acids on mouse CMV (MCMV) replication. In primary mouse hepatocytes, physiological concentrations of taurochenodeoxycholic acid (TCDC), glycochenodeoxycholic acid, and to a lesser extent taurocholic acid significantly reduced MCMV-induced gene expression and diminished the generation of virus progeny, while several other bile acids did not exert antiviral effects. The anticytomegalovirus activity required active import of bile acids via the sodium-taurocholate-cotransporting polypeptide (NTCP) and was consistently observed in hepatocytes but not in fibroblasts. Under conditions in which alpha interferon (IFN-α) lacks antiviral activity, physiological TCDC concentrations were similarly effective as IFN-γ. A detailed investigation of distinct steps of the viral life cycle revealed that TCDC deregulates viral transcription and diminishes global translation in infected cells.
Cytomegaloviruses are members of the Betaherpesvirinae subfamily. Primary infection leads to latency, from which cytomegaloviruses can reactivate under immunocompromised conditions and cause severe disease manifestations, including hepatitis. The present study describes an unanticipated antiviral activity of conjugated bile acids on MCMV replication in hepatocytes. Bile acids negatively influence viral transcription and exhibit a global effect on translation. Our data identify bile acids as site-specific soluble host restriction factors against MCMV, which may allow rational design of anticytomegalovirus drugs using bile acids as lead compounds.
肝脏是巨细胞病毒（CMV）复制和潜伏的主要部位。肝细胞产生、分泌并循环利用一系列化学性质各异的胆汁酸，因此胆汁酸与巨细胞病毒之间不可避免地会发生相互作用。在此，我们确定了天然存在的胆汁酸对小鼠巨细胞病毒（MCMV）复制的影响。在原代小鼠肝细胞中，牛磺鹅去氧胆酸（TCDC）、甘氨鹅去氧胆酸的生理浓度，以及在较小程度上牛磺胆酸的生理浓度，均显著降低了MCMV诱导的基因表达，并减少了病毒子代的产生，而其他几种胆汁酸则没有发挥抗病毒作用。抗巨细胞病毒活性需要胆汁酸通过牛磺胆酸钠共转运多肽（NTCP）进行主动摄取，并且在肝细胞中始终观察到这种现象，而在成纤维细胞中则未观察到。在α干扰素（IFN-α）缺乏抗病毒活性的条件下，生理浓度的TCDC与IFN-γ同样有效。对病毒生命周期不同步骤的详细研究表明，TCDC会使受感染细胞中的病毒转录失调，并减少整体翻译。
巨细胞病毒是β疱疹病毒亚科的成员。初次感染会导致潜伏，在免疫功能低下的情况下，巨细胞病毒可重新激活并引发严重的疾病表现，包括肝炎。本研究描述了结合型胆汁酸对肝细胞中MCMV复制具有意想不到的抗病毒活性。胆汁酸对病毒转录产生负面影响，并对翻译具有整体影响。我们的数据将胆汁酸确定为针对MCMV的位点特异性可溶性宿主限制因子，这可能有助于以胆汁酸为先导化合物合理设计抗巨细胞病毒药物。
