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

Cell. 2020 Aug 6;182(3):734-743.e5. doi: 10.1016/j.cell.2020.06.010. Epub 2020 Jun 10.

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.

Keywords: COVID-19; SARS-CoV-2; mouse model; pathogenesis; therapeutics; vaccine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Betacoronavirus / immunology*
  • Chlorocebus aethiops
  • Coronavirus Infections / pathology*
  • Coronavirus Infections / prevention & control*
  • Coronavirus Infections / virology
  • Disease Models, Animal*
  • Drug Evaluation, Preclinical / methods
  • Female
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Lung / pathology
  • Lung / virology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pandemics / prevention & control*
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • Pneumonia, Viral / pathology*
  • Pneumonia, Viral / prevention & control*
  • Pneumonia, Viral / virology
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • Specific Pathogen-Free Organisms
  • Transduction, Genetic
  • Vaccination*
  • Vero Cells
  • Viral Load
  • Virus Replication

Substances

  • IFNG protein, mouse
  • Ifnar1 protein, mouse
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Receptor, Interferon alpha-beta
  • Interferon-gamma
  • Peptidyl-Dipeptidase A
  • angiotensin converting enzyme 2

Supplementary concepts

  • COVID-19
  • severe acute respiratory syndrome coronavirus 2