Respiratory Syncytial Virus Replication Is Promoted by Autophagy-Mediated Inhibition of Apoptosis

• Published in: Journal of virology Vol. 92; no. 8
• Main Authors: Li, Miao, Li, Jian, Zeng, Ruihong, Yang, Jianling, Liu, Jianguo, Zhang, Zhengzheng, Song, Xiaotian, Yao, Zhiyan, Ma, Cuiqing, Li, Wenjian, Wang, Kai, Wei, Lin
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 15-04-2018
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; AMP-Activated Protein Kinases - metabolism; Apoptosis; Autophagy; Autophagy-Related Protein 5 - metabolism; Autophagy-Related Protein 7 - metabolism; Beclin-1 - metabolism; Cell Line; Humans; Respiratory Syncytial Virus Infections - metabolism; Respiratory Syncytial Virus Infections - pathology; Respiratory Syncytial Viruses - physiology; TOR Serine-Threonine Kinases - metabolism; Virus Replication; Virus-Cell Interactions; apoptosis; autophagy; RSV; virus replication; ROS
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/jvi.02193-17

Respiratory syncytial virus (RSV) is the main cause of acute lower respiratory tract infection (ALRI) in children worldwide. Virus-host interactions affect the progression and prognosis of the infection. Autophagy plays important roles in virus-host interactions. Respiratory epithelial cells serve as the front line of host defense during RSV infection, However, it is still unclear how they interact with RSV. In this study, we found that RSV induced autophagy that favored RSV replication and exacerbated lung pathology
Mechanistically, RSV induced complete autophagy flux through reactive oxygen species (ROS) generation and activation of the AMP-activated protein kinase/mammalian target of rapamycin (AMPK-MTOR) signaling pathway in HEp-2 cells. Furthermore, we evaluated the functions of autophagy in RSV replication and found that RSV replication was increased in HEp-2 cells treated with rapamycin but decreased remarkably in cells treated with 3-methylademine (3-MA) or wortmannin. Knockdown key molecules in the autophagy pathway with short hairpinp RNA (shRNA) against autophagy-related gene 5 (
), autophagy-related gene 7 (
), or
or treatment with ROS scavenger N-acetyl-l-cysteine (NAC) and AMPK inhibitor (compound C) suppressed RSV replication. 3-MA or sh
significantly decreased cell viability and increased cell apoptosis at 48 hours postinfection (hpi). Blocking apoptosis with Z-VAD-FMK partially restored virus replication at 48 hpi. Those results provide strong evidence that autophagy may function as a proviral mechanism in a cell-intrinsic manner during RSV infection.
An understanding of the mechanisms that respiratory syncytial virus utilizes to interact with respiratory epithelial cells is critical to the development of novel antiviral strategies. In this study, we found that RSV induces autophagy through a ROS-AMPK signaling axis, which in turn promotes viral infection. Autophagy favors RSV replication through blocking cell apoptosis at 48 hpi. Mechanistically, RSV induces mitophagy, which maintains mitochondrial homeostasis and therefore decreases cytochrome
release and apoptosis induction. This study provides a novel insight into this virus-host interaction, which may help to exploit new antiviral treatments targeting autophagy processes.