A SCID mouse-human lung xenograft model of SARS-CoV-2 infection
Wenkun Fu, Wei Wang, Lunzhi Yuan, Yanzhen Lin, Xiumin Huang, Rirong Chen, Minping Cai, Che Liu, Liqiang Chen, Ming Zhou, Kun Wu, Huan Zhao, Dequan Pan, Jian Ma, Junping Hong, Bingke Zhai, Yali Zhang, Zhibo Kong, Yingbin Wang, Yixin Chen, Quan Yuan, Huachen Zhu, Tong Cheng, Yi Guan, Ningshao Xia
Abstract
SARS-CoV-2 infection, which is responsible for the current COVID-19 pandemic, can cause lifethreatening pneumonia, respiratory failure and even death. Characterizing SARS-CoV-2 pathogenesis in primary human target cells and tissues is crucial for developing vaccines and therapeutics. However, given the limited access to clinical samples from COVID-19 patients, there is a pressing need for in vitro/in vivo models to investigate authentic SARS-CoV-2 infection in primary human lung cells or tissues with mature structures. The present study was designed to evaluate a humanized mouse model carrying human lung xenografts for SARS-CoV-2 infection in vivo. Methods: Human fetal lung tissue surgically grafted under the dorsal skin of SCID mice were assessed for growth and development after 8 weeks. Following SARS-CoV-2 inoculation into the differentiated lung xenografts, viral replication, cell-type tropism and histopathology of SARS-CoV-2 infection, and local cytokine/chemokine expression were determined over a 6-day period. The effect of IFN- treatment against SARS-CoV-2 infection was tested in the lung xenografts. Results: Human lung xenografts expanded and developed mature structures closely resembling normal human lung. SARS-CoV-2 replicated and spread efficiently in the lung xenografts with the epithelial cells as the main target, caused severe lung damage, and induced a robust pro-inflammatory response. IFN- treatment effectively inhibited SARS-CoV-2 replication in the lung xenografts. Conclusions: These data support the human lung xenograft mouse model as a useful and biological relevant tool that should facilitate studies on the pathogenesis of SARS-CoV-2 lung infection and the evaluation of potential antiviral therapies.