Enhancing human ACE2 expression in mouse models to improve COVID-19 research

Area of Science:

• Biomedical Research
• Infectious Disease Modeling
• Genetics and Genomics

Background:

• Wild-type mice lack susceptibility to SARS-CoV-2 due to low affinity of mouse ACE2.
• Existing human ACE2 (hACE2) mouse models show limited expression, hindering COVID-19 manifestation mimicry.

Purpose of the Study:

• To develop and compare novel hACE2 mouse models for enhanced SARS-CoV-2 research.
• To investigate the impact of genetic engineering strategies on hACE2 expression and function.

Main Methods:

• Generation of hACE2 mouse models using different strategies, including β-globin insertion and codon optimization (opt-hACE2).
• Comparative analysis of hACE2 expression levels and tissue distribution.
• Assessment of immune responses and COVID-19 phenotypes following SARS-CoV-2 challenge.

Main Results:

• Downstream β-globin insertion significantly enhanced hACE2 transgene transcription.
• Codon optimization (opt-hACE2) improved hACE2 translation efficiency across multiple tissues.
• opt-hACE2 mice exhibited more robust immune responses and severe COVID-19 phenotypes.

Conclusions:

• Genetic strategies, including β-globin elements and codon optimization, critically influence hACE2 expression in mouse models.
• Optimized hACE2 mice represent valuable tools for studying SARS-CoV-2 pathogenesis and evaluating therapeutics.