Enterovirus 71-induced autophagy increases viral replication and pathogenesis in a suckling mouse model

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• 作者：Ying-Ray Lee (1)
  Po-Shun Wang (2)
  Jen-Ren Wang (3) (4)
  Hsiao-Sheng Liu (2) (4)
  
  1. Department of Medical Research ; Chiayi Christian Hospital ; Chiayi ; Taiwan
  2. Department of Microbiology and Immunology ; College of Medicine ; National Cheng Kung University ; Tainan ; Taiwan
  3. Department of Medical Laboratory Science and Biotechnology ; College of Medicine ; National Cheng Kung University ; Tainan ; Taiwan
  4. Center of Infectious Disease and Signaling Research ; College of Medicine ; National Cheng Kung University ; Tainan ; Taiwan
  
• 关键词：EV71 ; Autophagy ; Amphisome ; Suckling mice
• 刊名：Journal of Biomedical Science
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：21
• 期：1
• 全文大小：3,091 KB
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• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Biomedicine
  
• 出版者：Springer Netherlands
• ISSN：1423-0127

文摘

Background We previously reported that Enterovirus 71 (EV71) infection activates autophagy, which promotes viral replication both in vitro and in vivo. In the present study we further investigated whether EV71 infection of neuronal SK-N-SH cells induces an autophagic flux. Furthermore, the effects of autophagy on EV71-related pathogenesis and viral load were evaluated after intracranial inoculation of mouse-adapted EV71 (MP4 strain) into 6-day-old ICR suckling mice. Results We demonstrated that in EV71-infected SK-N-SH cells, EV71 structural protein VP1 and nonstructural protein 2C co-localized with LC3 and mannose-6-phosphate receptor (MPR, endosome marker) proteins by immunofluorescence staining, indicating amphisome formation. Together with amphisome formation, EV71 induced an autophagic flux, which could be blocked by NH4Cl (inhibitor of acidification) and vinblastine (inhibitor of fusion), as demonstrated by Western blotting. Suckling mice intracranially inoculated with EV71 showed EV71 VP1 protein expression (representing EV71 infection) in the cerebellum, medulla, and pons by immunohistochemical staining. Accompanied with these infected brain tissues, increased expression of LC3-II protein as well as formation of LC3 aggregates, autophagosomes and amphisomes were detected. Amphisome formation, which was confirmed by colocalization of EV71-VP1 protein or LC3 puncta and the endosome marker protein MPR. Thus, EV71-infected suckling mice (similar to EV71-infected SK-N-SH cells) also show an autophagic flux. The physiopathological parameters of EV71-MP4 infected mice, including body weight loss, disease symptoms, and mortality were increased compared to those of the uninfected mice. We further blocked EV71-induced autophagy with the inhibitor 3-methyladenine (3-MA), which attenuated the disease symptoms and decreased the viral load in the brain tissues of the infected mice. Conclusions In this study, we reveal that EV71 infection of suckling mice induces an amphisome formation accompanied with the autophagic flux in the brain tissues. Autophagy induced by EV71 promotes viral replication and EV71-related pathogenesis.