Division of Infectious Diseases, Department of Medicine, and the Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
PLoS Pathog. 2013;9(5):e1003345. doi: 10.1371/journal.ppat.1003345. Epub 2013 May 23.
Persistent infections with hepatitis C virus (HCV) may result in life-threatening liver disease, including cirrhosis and cancer, and impose an important burden on human health. Understanding how the virus is capable of achieving persistence in the majority of those infected is thus an important goal. Although HCV has evolved multiple mechanisms to disrupt and block cellular signaling pathways involved in the induction of interferon (IFN) responses, IFN-stimulated gene (ISG) expression is typically prominent in the HCV-infected liver. Here, we show that Toll-like receptor 3 (TLR3) expressed within uninfected hepatocytes is capable of sensing infection in adjacent cells, initiating a local antiviral response that partially restricts HCV replication. We demonstrate that this is dependent upon the expression of class A scavenger receptor type 1 (MSR1). MSR1 binds extracellular dsRNA, mediating its endocytosis and transport toward the endosome where it is engaged by TLR3, thereby triggering IFN responses in both infected and uninfected cells. RNAi-mediated knockdown of MSR1 expression blocks TLR3 sensing of HCV in infected hepatocyte cultures, leading to increased cellular permissiveness to virus infection. Exogenous expression of Myc-MSR1 restores TLR3 signaling in MSR1-depleted cells with subsequent induction of an antiviral state. A series of conserved basic residues within the carboxy-terminus of the collagen superfamily domain of MSR1 are required for binding and transport of dsRNA, and likely facilitate acidification-dependent release of dsRNA at the site of TLR3 expression in the endosome. Our findings reveal MSR1 to be a critical component of a TLR3-mediated pattern recognition receptor response that exerts an antiviral state in both infected and uninfected hepatocytes, thereby limiting the impact of HCV proteins that disrupt IFN signaling in infected cells and restricting the spread of HCV within the liver.
持续性丙型肝炎病毒（HCV）感染可能导致危及生命的肝脏疾病，包括肝硬化和肝癌，并对人类健康造成重大负担。因此，了解病毒如何能够在大多数感染者中持续存在是一个重要的目标。尽管 HCV 已经进化出多种机制来破坏和阻断参与干扰素（IFN）反应诱导的细胞信号通路，但 IFN 刺激基因（ISG）的表达在 HCV 感染的肝脏中通常很显著。在这里，我们表明，未感染肝细胞内表达的 Toll 样受体 3（TLR3）能够感知相邻细胞中的感染，启动局部抗病毒反应，部分限制 HCV 复制。我们证明这依赖于 A 类清道夫受体 1（MSR1）的表达。MSR1 结合细胞外双链 RNA，介导其内化和向内体的运输，在那里它与 TLR3 结合，从而在感染和未感染的细胞中触发 IFN 反应。MSR1 表达的 RNAi 介导敲低阻断 TLR3 对 HCV 的感知，导致感染的肝细胞培养物中细胞对病毒感染的易感性增加。Myc-MSR1 的外源性表达在 MSR1 耗尽的细胞中恢复 TLR3 信号转导，随后诱导抗病毒状态。MSR1 胶原超家族结构域羧基末端的一系列保守碱性残基对于 dsRNA 的结合和运输是必需的，并且可能有助于 dsRNA 在 TLR3 表达的内体部位酸化依赖性释放。我们的研究结果表明，MSR1 是 TLR3 介导的模式识别受体反应的关键组成部分，在感染和未感染的肝细胞中发挥抗病毒状态，从而限制了 HCV 蛋白破坏感染细胞中 IFN 信号的影响，并限制了 HCV 在肝脏内的传播。
