PMID- 34550769 OWN - NLM STAT- MEDLINE DCOM- 20211213 LR - 20231108 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 95 IP - 24 DP - 2021 Nov 23 TI - Inhibition of Autophagy Suppresses SARS-CoV-2 Replication and Ameliorates Pneumonia in hACE2 Transgenic Mice and Xenografted Human Lung Tissues. PG - e0153721 LID - 10.1128/JVI.01537-21 [doi] LID - e01537-21 AB - Autophagy is thought to be involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, how SARS-CoV-2 interferes with the autophagic pathway and whether autophagy contributes to virus infection in vivo is unclear. In this study, we identified SARS-CoV-2-triggered autophagy in animal models, including the long-tailed or crab-eating macaque (Macaca fascicularis), human angiotensin-converting enzyme 2 (hACE2) transgenic mice, and xenografted human lung tissues. In Vero E6 and Huh-7 cells, SARS-CoV-2 induces autophagosome formation, accompanied by consistent autophagic events, including inhibition of the Akt-mTOR pathway and activation of the ULK-1-Atg13 and VPS34-VPS15-Beclin1 complexes, but it blocks autophagosome-lysosome fusion. Modulation of autophagic elements, including the VPS34 complex and Atg14, but not Atg5, inhibits SARS-CoV-2 replication. Moreover, this study represents the first to demonstrate that the mouse bearing xenografted human lung tissue is a suitable model for SARS-CoV-2 infection and that autophagy inhibition suppresses SARS-CoV-2 replication and ameliorates virus-associated pneumonia in human lung tissues. We also observed a critical role of autophagy in SARS-CoV-2 infection in an hACE2 transgenic mouse model. This study, therefore, gives insights into the mechanisms by which SARS-CoV-2 manipulates autophagosome formation, and we suggest that autophagy-inhibiting agents might be useful as therapeutic agents against SARS-CoV-2 infection. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with limited therapeutics. Insights into the virus-host interactions contribute substantially to the development of anti-SARS-CoV-2 therapeutics. The novelty of this study is the use of a new animal model: mice xenografted with human lung tissues. Using a combination of in vitro and in vivo studies, we have obtained experimental evidence that induction of autophagy contributes to SARS-CoV-2 infection and improves our understanding of potential therapeutic targets for SARS-CoV-2. FAU - Shang, Chao AU - Shang C AD - Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People's Republic of China. FAU - Zhuang, Xinyu AU - Zhuang X AD - Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People's Republic of China. FAU - Zhang, He AU - Zhang H AD - Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People's Republic of China. FAU - Li, Yiquan AU - Li Y AD - Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People's Republic of China. FAU - Zhu, Yilong AU - Zhu Y AD - Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People's Republic of China. FAU - Lu, Jing AU - Lu J AD - Agricultural College, Yanbian University, Yanji, People's Republic of China. FAU - Ge, Chenchen AU - Ge C AD - Agricultural College, Yanbian University, Yanji, People's Republic of China. FAU - Cong, Jianan AU - Cong J AD - Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People's Republic of China. FAU - Li, Tingyu AU - Li T AD - Agricultural College, Yanbian University, Yanji, People's Republic of China. FAU - Li, Nan AU - Li N AD - Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People's Republic of China. FAU - Tian, Mingyao AU - Tian M AD - Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People's Republic of China. FAU - Jin, Ningyi AU - Jin N AD - Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People's Republic of China. AD - Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People's Republic of China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China. FAU - Li, Xiao AU - Li X AD - Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People's Republic of China. AD - Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People's Republic of China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China. LA - eng GR - 20YF003/Research and Development of New Coronavirus Pneumonia Recombinant Protein Vaccine/ GR - SQ2020YFF0417940/Key Project of Science and Technology Boosting Economy in 2020/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210922 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (RNA, Small Interfering) RN - EC 3.4.17.23 (ACE2 protein, human) RN - EC 3.4.17.23 (Ace2 protein, mouse) RN - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2) SB - IM MH - Angiotensin-Converting Enzyme 2/*genetics/metabolism MH - Animals MH - Autophagosomes MH - *Autophagy MH - COVID-19/*virology MH - Cell Line, Tumor MH - Chlorocebus aethiops MH - Humans MH - Lung/pathology/*virology MH - Macaca MH - Male MH - Mice MH - Mice, Transgenic MH - Pneumonia, Viral/drug therapy MH - RNA, Small Interfering/metabolism MH - *SARS-CoV-2 MH - Vero Cells MH - *Virus Replication MH - *COVID-19 Drug Treatment PMC - PMC8610582 OTO - NOTNLM OT - 3-MA OT - SARS-CoV-2 OT - VPS34 OT - animal model OT - autophagy EDAT- 2021/09/23 06:00 MHDA- 2021/12/15 06:00 PMCR- 2021/11/23 CRDT- 2021/09/22 17:16 PHST- 2021/09/23 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/09/22 17:16 [entrez] PHST- 2021/11/23 00:00 [pmc-release] AID - 01537-21 [pii] AID - jvi.01537-21 [pii] AID - 10.1128/JVI.01537-21 [doi] PST - ppublish SO - J Virol. 2021 Nov 23;95(24):e0153721. doi: 10.1128/JVI.01537-21. Epub 2021 Sep 22.