Inhibition of autophagy suppresses SARS-CoV-2 replication and ameliorates pneumonia in hACE2 transgenic mice and xenografted human lung tissues

Shang, Chao; Zhuang, Xinyu; Zhang, He; Li, Yiquan; Zhu, Yilong; Lu, Jing; Ge, Chenchen; Cong, Jianan; Li, Tingyu; Li, Nan; Tian, Mingyao; Jin, Ningyi; Li, Xiao

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. Here, we identified SARS-CoV-2-triggered autophagy in animal models including the long tailed or crab eating macaque (Macaca fascicularis), 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 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 contributes substantially. The novelty of this report is the use of a new animal model: mice xenografted with human lung tissues. Using a combination of the in vitro and in vivo studies, we have provided experimental evidence that induction of autophagy contributes to SARS-CoV-2 infection and improves our understanding of potential therapeutic targets for SARS-CoV-2.