Generation of a Broadly Useful Model for COVID-19 Pathogenesis, Vaccination, and Treatment

Jing Sun1, Zhen Zhuang1, Jian Zheng2, Kun Li2, Roy Lok-Yin Wong2, Donglan Liu1, Jicheng Huang3, Jiangping He4, Airu Zhu1, Jingxian Zhao1, Xiaobo Li3, Yin Xi1, Rongchang Chen5, Abeer N Alshukairi6, Zhao Chen1, Zhaoyong Zhang1, Chunke Chen1, Xiaofang Huang1, Fang Li1, Xiaomin Lai1, Dingbin Chen1, Liyan Wen1, Jianfen Zhuo1, Yanjun Zhang1, Yanqun Wang1, Shuxiang Huang3, Jun Dai3, Yongxia Shi3, Kui Zheng3, Mariah R Leidinger7, Jiekai Chen8, Yimin Li1, Nanshan Zhong1, David K Meyerholz7, Paul B McCray Jr9, Stanley Perlman10, Jincun Zhao11

  1. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510182, China.
  2. Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa 52242, USA.
  3. Guangzhou Customs District Technology Center, Guangzhou 510700, China.
  4. Guangzhou Regenerative Medicine and Health-Guangdong Laboratory (GRMH-GDL), Guangzhou 510530, China.
  5. Shenzhen Institute of Respiratory Disease, First Affiliated Hospital of South University of Science and Technology of China (Shenzhen People's Hospital), Shenzhen, Guangdong, China.
  6. King Faisal Specialist Hospital and Research Centre, Jeddah, Kingdom of Saudi Arabia.
  7. Department of Pathology, University of Iowa, Iowa City, Iowa 52242, USA.
  8. Guangzhou Regenerative Medicine and Health-Guangdong Laboratory (GRMH-GDL), Guangzhou 510530, China; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  9. Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa 52242, USA; Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA. Electronic address: paul-mccray@uiowa.edu.
  10. Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa 52242, USA; Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA. Electronic address: stanley-perlman@uiowa.edu.
  11. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510182, China; Institute of Infectious Disease, Guangzhou Eighth People's Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510060, China. Electronic address: zhaojincun@gird.cn.

Abstract

COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.

Presented By Roy Lok-Yin Wong | ORCID iD

COVID-19Nicholas Liao2020-08 (Aug)