Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA.
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA.
Semin Cell Dev Biol. 2020 May;101:20-35. doi: 10.1016/j.semcdb.2019.07.015. Epub 2019 Aug 8.
The molecular mechanism(s) how liver damage during the chronic hepatitis C virus (HCV) infection evolve into cirrhosis and hepatocellular carcinoma (HCC) is unclear. HCV infects hepatocyte, the major cell types in the liver. During infection, large amounts of viral proteins and RNA replication intermediates accumulate in the endoplasmic reticulum (ER) of the infected hepatocyte, which creates a substantial amount of stress response. Infected hepatocyte activates a different type of stress adaptive mechanisms such as unfolded protein response (UPR), antioxidant response (AR), and the integrated stress response (ISR) to promote virus-host cell survival. The hepatic stress is also amplified by another layer of innate and inflammatory response associated with cellular sensing of virus infection through the production of interferon (IFN) and inflammatory cytokines. The interplay between various types of cellular stress signal leads to different forms of cell death such as apoptosis, necrosis, and autophagy depending on the intensity of the stress and nature of the adaptive cellular response. How do the adaptive cellular responses decode such death programs that promote host-microbe survival leading to the establishment of chronic liver disease? In this review, we discuss how the adaptive cellular response through the Nrf2 pathway that promotes virus and cell survival. Furthermore, we provide a glimpse of novel stress-induced Nrf2 mediated compensatory autophagy mechanisms in virus-cell survival that degrade tumor suppressor gene and activation of oncogenic signaling during HCV infection. Based on these facts, we hypothesize that the balance between hepatic stress, inflammation and different types of cell death determines liver disease progression outcomes. We propose that a more nuanced understanding of virus-host interactions under excessive cellular stress may provide an answer to the fundamental questions why some individuals with chronic HCV infection remain at risk of developing cirrhosis, cancer and some do not.
慢性丙型肝炎病毒 (HCV) 感染导致肝损伤的分子机制如何演变为肝硬化和肝细胞癌 (HCC) 尚不清楚。HCV 感染肝细胞，这是肝脏中的主要细胞类型。在感染过程中，大量的病毒蛋白和 RNA 复制中间体在受感染的肝细胞的内质网 (ER) 中积累，这会产生大量的应激反应。受感染的肝细胞激活不同类型的应激适应性机制，如未折叠蛋白反应 (UPR)、抗氧化反应 (AR) 和整合应激反应 (ISR)，以促进病毒-宿主细胞存活。肝应激还通过与细胞对病毒感染的感应相关的先天和炎症反应的另一层放大，通过产生干扰素 (IFN) 和炎症细胞因子。各种类型的细胞应激信号的相互作用导致不同形式的细胞死亡，如凋亡、坏死和自噬，这取决于应激的强度和适应性细胞反应的性质。适应性细胞反应如何解码促进宿主-微生物存活的这些死亡程序，从而导致慢性肝病的建立？在这篇综述中，我们讨论了适应性细胞反应如何通过促进病毒和细胞存活的 Nrf2 途径发挥作用。此外，我们还提供了一个新的视角，即在 HCV 感染过程中，应激诱导的 Nrf2 介导的补偿性自噬机制如何降解肿瘤抑制基因并激活致癌信号。基于这些事实，我们假设肝应激、炎症和不同类型的细胞死亡之间的平衡决定了肝病进展的结果。我们假设，对过度细胞应激下病毒-宿主相互作用的更细致理解可能为为什么一些慢性 HCV 感染个体仍然面临发展为肝硬化、癌症的风险，而另一些个体则没有的基本问题提供答案。
