Rapid generation of mouse model for emerging infectious disease with the case of severe COVID-19

Sun, Cheng-Pu; Jan, Jia-Tsrong; Wang, I-Hsuan; Ma, Hsiu-Hua; Ko, Hui-Ying; Wu, Ping-Yi; Kuo, Tzu-Jiun; Liao, Hsin-Ni; Lan, Yu-Hua; Sie, Zong-Lin; Chen, Yen-Hui; Ko, Yi-An; Liao, Chun-Che; Chen, Liang-Yu; Lee, I-Jung; Tsung, Szu-I; Lai, Yun-Ju; Chiang, Ming-Tsai; Liang, Jian-Jong; Liu, Wen-Chun; Wang, Jing-Rong; Yuan, Joyce Pei-Yi; Lin, Yin-Shiou; Tsai, Yi-Ching; Hsieh, Shie-Liang; Li, Chia-Wei; Wu, Han-Chung; Ko, Tai-Ming; Lin, Yi-Ling; Tao, Mi-Hua

Since the pandemic of COVID-19 has intensely struck human society, small animal model for this infectious disease is in urgent need for basic and pharmaceutical research. Although several COVID-19 animal models have been identified, many of them show either minimal or inadequate pathophysiology after SARS-CoV-2 challenge. Here, we describe a new and versatile strategy to rapidly establish a mouse model for emerging infectious diseases in one month by multi-route, multi-serotype transduction with recombinant adeno-associated virus (AAV) vectors expressing viral receptor. In this study, the proposed approach enables profound and enduring systemic expression of SARS-CoV-2-receptor hACE2 in wild-type mice and renders them vulnerable to SARS-CoV-2 infection. Upon virus challenge, generated AAV/hACE2 mice showed pathophysiology closely mimicking the patients with severe COVID-19. The efficacy of a novel therapeutic antibody cocktail RBD-chAbs for COVID-19 was tested and confirmed by using this AAV/hACE2 mouse model, further demonstrating its successful application in drug development.