Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Viral Immunol. 2021 May;34(4):241-255. doi: 10.1089/vim.2020.0024. Epub 2021 Feb 9.
Autophagy is involved in the pathogenesis of multiple pathogen infection. Previous studies have reported that human cytomegalovirus (CMV) activates autophagy in the early stage of infection and then inhibits autophagy. Little is known about the role of autophagy in murine CMV (MCMV) infection, especially in MCMV-induced hepatitis. The purpose of this study is to investigate the role of autophagy in MCMV hepatitis. BALB/c mice were infected with MCMV and a series of experiments involving western blot, immunofluorescence, immunohistochemistry, H&E (Hematoxylin and Eosin) staining and quantitative real-time polymerase chain reaction were performed in this study. The expression of SQSTM1/p62, PI3K, the ratio of phosphorylated Akt to total Akt, and the ratio of phosphorylated mammalian target of rapamycin (mTOR) to total mTOR were increased, and the expression of light-chain 3 (LC3)-II were decreased in the livers of infected mice on days 3 and 7 postinfection (p.i.). Compared with the untreated infected group, increased transcription level of MCMV glycoprotein B (gB), increased expression levels of interleukin1-β (IL-1β), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), decreased expression level of type I interferon α (IFN-α), as well as aggravated liver pathological injury were detected in starvation-treated infected group on days 3 and 7 p.i.; whereas decreased transcription level of MCMV gB, decreased expression levels of IL-1β, AST and ALT, increased expression level of type I IFN-α, as well as alleviated liver pathological injury were detected in chloroquine (CQ)-treated infected group on day 3 p.i. In conclusion, autophagy is inhibited through activating the PI3K/Akt/mTOR pathway in the liver of BALB/c mice during MCMV infection, and autophagy may promote MCMV replication and aggravate liver pathological damage and inflammation. Further understanding of the interactions between autophagy and MCMV infection and its potential mechanism may bring new important cues to the control of MCMV infection and antiviral therapy.
自噬参与多种病原体感染的发病机制。先前的研究报道，人类巨细胞病毒（CMV）在感染早期激活自噬，然后抑制自噬。关于自噬在鼠巨细胞病毒（MCMV）感染中的作用知之甚少，特别是在 MCMV 诱导的肝炎中。本研究旨在探讨自噬在 MCMV 肝炎中的作用。本研究采用 BALB/c 小鼠感染 MCMV，进行 Western blot、免疫荧光、免疫组化、H&E（苏木精和伊红）染色和定量实时聚合酶链反应等一系列实验。结果发现，感染后第 3 和第 7 天，感染小鼠肝脏中 SQSTM1/p62、PI3K、磷酸化 Akt 与总 Akt 的比值和磷酸化哺乳动物雷帕霉素靶蛋白（mTOR）与总 mTOR 的比值增加，LC3-II 的表达减少。与未处理的感染组相比，饥饿处理的感染组在感染后第 3 和第 7 天检测到 MCMV 糖蛋白 B（gB）转录水平增加、白细胞介素 1-β（IL-1β）、天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）表达水平增加、I 型干扰素α（IFN-α）表达水平降低以及肝脏病理损伤加重；而氯喹（CQ）处理的感染组在感染后第 3 天检测到 MCMV gB 转录水平降低、IL-1β、AST 和 ALT 表达水平降低、I 型 IFN-α表达水平升高以及肝脏病理损伤减轻。综上所述，在 MCMV 感染的 BALB/c 小鼠肝脏中，自噬通过激活 PI3K/Akt/mTOR 通路而受到抑制，自噬可能促进 MCMV 复制并加重肝脏病理损伤和炎症。进一步了解自噬与 MCMV 感染的相互作用及其潜在机制，可能为控制 MCMV 感染和抗病毒治疗带来新的重要线索。
