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

PLoS Pathog. 2021 Aug 11;17(8):e1009758. doi: 10.1371/journal.ppat.1009758. eCollection 2021 Aug.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Angiotensin-Converting Enzyme 2 / genetics
  • Animals
  • Antibodies, Viral / immunology
  • Antibodies, Viral / therapeutic use
  • COVID-19* / immunology
  • COVID-19* / pathology
  • COVID-19* / physiopathology
  • Chlorocebus aethiops
  • Communicable Diseases, Emerging*
  • Dependovirus / genetics
  • Disease Models, Animal*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Transduction, Genetic
  • Vero Cells

Substances

  • Antibodies, Viral
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2

Grants and funding

This research was supported by the funding supports from Taiwan Ministry of Science and Technology, Taiwan for COVID-19 study (MOST 109-3114-Y-001-001). M.H.T. was also supported by Academia Sinica Biomedical Translation Research Center (AS-KPQ-110-EIMD), and Y.L.L. was supported by Academia Sinica and MOST 108-2320-B-001-030-MY3. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.