Generation of a SARS-CoV-2-susceptible mouse model using adenovirus vector expressing human angiotensin-converting enzyme 2 driven by an elongation factor 1α promoter with leftward orientation

Front Immunol. 2024 Dec 9:15:1440314. doi: 10.3389/fimmu.2024.1440314. eCollection 2024.

Abstract

Introduction: To analyze the molecular pathogenesis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a small animal model such as mice is needed: human angiotensin converting enzyme 2 (hACE2), the receptor of SARS-CoV-2, needs to be expressed in the respiratory tract of mice.

Methods: We conferred SARS-CoV-2 susceptibility in mice by using an adenoviral vector expressing hACE2 driven by an elongation factor 1α (EF1α) promoter with a leftward orientation.

Results: In this model, severe pneumonia like human COVID-19 was observed in SARS-CoV-2-infected mice, which was confirmed by dramatic infiltration of inflammatory cells in the lung with efficient viral replication. An early circulating strain of SARS-CoV-2 caused the most severe weight loss when compared to SARS-CoV-2 variants such as Alpha, Beta and Gamma, although histopathological findings, viral replication, and cytokine expression characteristics were comparable.

Discussion: We found that a distinct proteome of an early circulating strain infected lung characterized by elevated complement activation and blood coagulation, which were mild in other variants, can contribute to disease severity. Unraveling the specificity of early circulating SARS-CoV-2 strains is important in elucidating the origin of the pandemic.

Keywords: COVID-19; SARS-CoV-2; adenoviral vector; mouse model; proteomics.

MeSH terms

  • Adenoviridae* / genetics
  • Angiotensin-Converting Enzyme 2* / genetics
  • Angiotensin-Converting Enzyme 2* / metabolism
  • Animals
  • COVID-19* / genetics
  • COVID-19* / immunology
  • Disease Models, Animal*
  • Disease Susceptibility
  • Genetic Vectors* / genetics
  • Humans
  • Lung / pathology
  • Lung / virology
  • Mice
  • Peptide Elongation Factor 1 / genetics
  • Promoter Regions, Genetic*
  • SARS-CoV-2* / genetics
  • SARS-CoV-2* / physiology
  • Virus Replication

Substances

  • Angiotensin-Converting Enzyme 2
  • ACE2 protein, human
  • Peptide Elongation Factor 1

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported in part by a grant from the Japan Agency for Medical Research and Development (AMED) (Grant No. 20nk0101615h001), the Takeda Science Foundation, and the Tokyo Metropolitan Government, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.